Papel de la proteína quinasa C (PKC) en el crecimiento de células de leucemia linfoide aguda tipo B, en el soporte que les proporcionan las células stem mesenquimales y en su funcionalidad en un modelo in vitro de nicho leucémico
gráficas, ilustraciones, tablas
- Autores:
-
Vanegas Avendaño, Natalia-Del Pilar
- Tipo de recurso:
- Fecha de publicación:
- 2021
- Institución:
- Universidad Nacional de Colombia
- Repositorio:
- Universidad Nacional de Colombia
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.unal.edu.co:unal/80304
- Palabra clave:
- 610 - Medicina y salud
570 - Biología
Leucemia linfoblástica aguda de células B (LLA-B)
MSC del co-cultivo (MSC-CO)
Proteína quinasa C (PKC)
Nicho leucémico (NL)
Microambiente de la médula ósea (MO)
Senescencia reversible
Pro-inflamatorio
Mesenchymal stem cells (MSC)
B-cell acute lymphoblastic leukemia (B-ALL)
Leukemic niche (LN)
MSC from co-culture (MSC-CO)
Protein kinase C (PKC)
Bone marrow (BM) microenvironment
Reversible senescence
Pro-inflammatory
- Rights
- openAccess
- License
- Atribución-NoComercial 4.0 Internacional
| id |
UNACIONAL2_ac221f6e2d4cd29ff02952aaec2806b2 |
|---|---|
| oai_identifier_str |
oai:repositorio.unal.edu.co:unal/80304 |
| network_acronym_str |
UNACIONAL2 |
| network_name_str |
Universidad Nacional de Colombia |
| repository_id_str |
|
| dc.title.spa.fl_str_mv |
Papel de la proteína quinasa C (PKC) en el crecimiento de células de leucemia linfoide aguda tipo B, en el soporte que les proporcionan las células stem mesenquimales y en su funcionalidad en un modelo in vitro de nicho leucémico |
| dc.title.translated.eng.fl_str_mv |
Role of protein kinase C (PKC) in the growth of B-cell acute lymphoblastic leukemia cells, in the support provided by mesenchymal stem cells and in their functionality in an in vitro model of leukemic niche. |
| title |
Papel de la proteína quinasa C (PKC) en el crecimiento de células de leucemia linfoide aguda tipo B, en el soporte que les proporcionan las células stem mesenquimales y en su funcionalidad en un modelo in vitro de nicho leucémico |
| spellingShingle |
Papel de la proteína quinasa C (PKC) en el crecimiento de células de leucemia linfoide aguda tipo B, en el soporte que les proporcionan las células stem mesenquimales y en su funcionalidad en un modelo in vitro de nicho leucémico 610 - Medicina y salud 570 - Biología Leucemia linfoblástica aguda de células B (LLA-B) MSC del co-cultivo (MSC-CO) Proteína quinasa C (PKC) Nicho leucémico (NL) Microambiente de la médula ósea (MO) Senescencia reversible Pro-inflamatorio Mesenchymal stem cells (MSC) B-cell acute lymphoblastic leukemia (B-ALL) Leukemic niche (LN) MSC from co-culture (MSC-CO) Protein kinase C (PKC) Bone marrow (BM) microenvironment Reversible senescence Pro-inflammatory |
| title_short |
Papel de la proteína quinasa C (PKC) en el crecimiento de células de leucemia linfoide aguda tipo B, en el soporte que les proporcionan las células stem mesenquimales y en su funcionalidad en un modelo in vitro de nicho leucémico |
| title_full |
Papel de la proteína quinasa C (PKC) en el crecimiento de células de leucemia linfoide aguda tipo B, en el soporte que les proporcionan las células stem mesenquimales y en su funcionalidad en un modelo in vitro de nicho leucémico |
| title_fullStr |
Papel de la proteína quinasa C (PKC) en el crecimiento de células de leucemia linfoide aguda tipo B, en el soporte que les proporcionan las células stem mesenquimales y en su funcionalidad en un modelo in vitro de nicho leucémico |
| title_full_unstemmed |
Papel de la proteína quinasa C (PKC) en el crecimiento de células de leucemia linfoide aguda tipo B, en el soporte que les proporcionan las células stem mesenquimales y en su funcionalidad en un modelo in vitro de nicho leucémico |
| title_sort |
Papel de la proteína quinasa C (PKC) en el crecimiento de células de leucemia linfoide aguda tipo B, en el soporte que les proporcionan las células stem mesenquimales y en su funcionalidad en un modelo in vitro de nicho leucémico |
| dc.creator.fl_str_mv |
Vanegas Avendaño, Natalia-Del Pilar |
| dc.contributor.advisor.none.fl_str_mv |
Vernot, Jean-Paul |
| dc.contributor.author.none.fl_str_mv |
Vanegas Avendaño, Natalia-Del Pilar |
| dc.contributor.researchgroup.spa.fl_str_mv |
Fisiología Celular y Molecular |
| dc.subject.ddc.spa.fl_str_mv |
610 - Medicina y salud 570 - Biología |
| topic |
610 - Medicina y salud 570 - Biología Leucemia linfoblástica aguda de células B (LLA-B) MSC del co-cultivo (MSC-CO) Proteína quinasa C (PKC) Nicho leucémico (NL) Microambiente de la médula ósea (MO) Senescencia reversible Pro-inflamatorio Mesenchymal stem cells (MSC) B-cell acute lymphoblastic leukemia (B-ALL) Leukemic niche (LN) MSC from co-culture (MSC-CO) Protein kinase C (PKC) Bone marrow (BM) microenvironment Reversible senescence Pro-inflammatory |
| dc.subject.proposal.spa.fl_str_mv |
Leucemia linfoblástica aguda de células B (LLA-B) MSC del co-cultivo (MSC-CO) Proteína quinasa C (PKC) Nicho leucémico (NL) Microambiente de la médula ósea (MO) Senescencia reversible Pro-inflamatorio |
| dc.subject.proposal.eng.fl_str_mv |
Mesenchymal stem cells (MSC) B-cell acute lymphoblastic leukemia (B-ALL) Leukemic niche (LN) MSC from co-culture (MSC-CO) Protein kinase C (PKC) Bone marrow (BM) microenvironment Reversible senescence Pro-inflammatory |
| description |
gráficas, ilustraciones, tablas |
| publishDate |
2021 |
| dc.date.accessioned.none.fl_str_mv |
2021-09-24T22:20:14Z |
| dc.date.available.none.fl_str_mv |
2021-09-24T22:20:14Z |
| dc.date.issued.none.fl_str_mv |
2021 |
| dc.type.spa.fl_str_mv |
Trabajo de grado - Doctorado |
| dc.type.driver.spa.fl_str_mv |
info:eu-repo/semantics/masterThesis |
| dc.type.version.spa.fl_str_mv |
info:eu-repo/semantics/acceptedVersion |
| dc.type.content.spa.fl_str_mv |
Image Text |
| dc.type.redcol.spa.fl_str_mv |
http://purl.org/redcol/resource_type/TM |
| status_str |
acceptedVersion |
| dc.identifier.uri.none.fl_str_mv |
https://repositorio.unal.edu.co/handle/unal/80304 |
| dc.identifier.instname.spa.fl_str_mv |
Universidad Nacional de Colombia |
| dc.identifier.reponame.spa.fl_str_mv |
Repositorio Institucional Universidad Nacional de Colombia |
| dc.identifier.repourl.spa.fl_str_mv |
https://repositorio.unal.edu.co/ |
| url |
https://repositorio.unal.edu.co/handle/unal/80304 https://repositorio.unal.edu.co/ |
| identifier_str_mv |
Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia |
| dc.language.iso.spa.fl_str_mv |
spa |
| language |
spa |
| dc.relation.references.spa.fl_str_mv |
Abdul-Aziz, A. M., Shafat, M. S., Mehta, T. K., Di Palma, F., Lawes, M. J., Rushworth, S. A., y Bowles, K. M. (2017). MIF-induced stromal PKCβ/IL8 is essential in human acute myeloid leukemia. Cancer Research, 77(2). https://doi.org/10.1158/0008-5472.CAN-16-1095 Abdul-Aziz, A. M., Sun, Y., Hellmich, C., Marlein, C. R., Mistry, J., Forde, E., Piddock, R. E., Shafat, M. S., Morfakis, A., Mehta, T., Di Palma, F., Macaulay, I., Ingham, C. J., Haestier, A., Collins, A., Campisi, J., Bowles, K. M., y Rushworth, S. A. (2019). Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment. Blood, 133(5), 446-456. https://doi.org/10.1182/blood-2018-04-845420 Abrams, S. T., Lakum, T., Lin, K., Jones, G. M., Treweeke, A. T., Farahani, M., Hughes, M., Zuzel, M., y Slupsky, J. R. (2007). B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CβII. Blood, 109(3), 1193-1201. https://doi.org/10.1182/blood-2006-03-012021 Acuña, L., Sánchez, P., Uribe, D., Pulido, D., y Valencia, O. (2015). Situación del cáncer en Colombia 2015. https://doi.org/Book_Doi 10.1201/9781420072884 André, T., Meuleman, N., Stamatopoulos, B., De Bruyn, C., Pieters, K., Bron, D., y Lagneaux, L. (2013). Evidences of Early Senescence in Multiple Myeloma Bone Marrow Mesenchymal Stromal Cells. PLoS ONE, 8(3), e59756. https://doi.org/10.1371/journal.pone.0059756 Antonsson, A. y Persson, J. L. (2009). Induction of apoptosis by staurosporine involves the inhibition of expression of the major cell cycle proteins at the G(2)/m checkpoint accompanied by alterations in Erk and Akt kinase activities. Anticancer Res., 29(8), 2893-2898. http://www.ncbi.nlm.nih.gov/pubmed/19661292 Arnulf, B., Lecourt, S., Soulier, J., Ternaux, B., Lacassagne, M.-N., Crinquette, A., Dessoly, J., Sciaini, A.-K., Benbunan, M., Chomienne, C., Fermand, J.-P., Marolleau, J.-P., y Larghero, J. (2007). Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma. Leukemia, 21(1), 158-163. https://doi.org/10.1038/sj.leu.2404466 Arranz, L., Sánchez-Aguilera, A., Martín-Pérez, D., Isern, J., Langa, X., Tzankov, A., Lundberg, P., Muntión, S., Tzeng, Y. S., Lai, D. M., Schwaller, J., Skoda, R. C., y Méndez-Ferrer, S. (2014). Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature, 512(1). https://doi.org/10.1038/nature13383 Baker, R. G., Hayden, M. S., y Ghosh, S. (2011). NF-κB, inflammation, and metabolic disease. En Cell Metabolism. https://doi.org/10.1016/j.cmet.2010.12.008 Barragán, M., Bellosillo, B., Campàs, C., Colomer, D., Pons, G., y Gil, J. (2002). Involvement of protein kinase C and phosphatidylinositol 3–kinase pathways in the survival of B-cell chronic lymphocytic leukemia cells. Blood, 99(8), 2969-2976. https://doi.org/10.1182/blood.V99.8.2969 Baryawno, N., Przybylski, D., Kowalczyk, M. S., Kfoury, Y., Severe, N., Gustafsson, K., Kokkaliaris, K. D., Mercier, F., Tabaka, M., Hofree, M., Dionne, D., Papazian, A., Lee, D., Ashenberg, O., Subramanian, A., Vaishnav, E. D., Rozenblatt-Rosen, O., Regev, A., y Scadden, D. T. (2019). A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia. Cell, 177(7), 1915-1932.e16. https://doi.org/10.1016/j.cell.2019.04.040 Beauséjour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., y Campisi, J. (2003). Reversal of human cellular senescence: Roles of the p53 and p16 pathways. EMBO J, 22(16), 4212-4222. https://doi.org/10.1093/emboj/cdg417 Belmokhtar, C. A., Hillion, J., y Ségal-Bendirdjian, E. (2001). Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms. Oncogene, 20(26), 3354-3362. https://doi.org/10.1038/sj.onc.1204436 Ben-Neriah, Y. y Karin, M. (2011). Inflammation meets cancer, with NF-κB as the matchmaker. Nat. Immunol., 12(8), 715-723. https://doi.org/10.1038/ni.2060 Berenstein, R., Blau, O., Nogai, A., Waechter, M., Slonova, E., Schmidt-Hieber, M., Kunitz, A., Pezzutto, A., Doerken, B., y Blau, I. W. (2015). Multiple myeloma cells alter the senescence phenotype of bone marrow mesenchymal stromal cells under participation of the DLK1-DIO3 genomic region. BMC Cancer, 15(1), 68. https://doi.org/10.1186/s12885-015-1078-3 Bernardo, M. E., Zaffaroni, N., Novara, F., Cometa, A. M., Avanzini, M. A., Moretta, A., Montagna, D., Maccario, R., Villa, R., Daidone, M. G., Zuffardi, O., y Locatelli, F. (2007). Human bone marrow-derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-06-4690 Bhat, A. H., Dar, K. B., Anees, S., Zargar, M. A., Masood, A., Sofi, M. A., y Ganie, S. A. (2015). Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. En Biomedicine and Pharmacotherapy (Vol. 74). https://doi.org/10.1016/j.biopha.2015.07.025 Bhatia, B., Multani, A. S., Patrawala, L., Chen, X., Calhoun-Davis, T., Zhou, J., Schroeder, L., Schneider-Broussard, R., Shen, J., Pathak, S., Chang, S., y Tang, D. G. (2007). Evidence that senescent human prostate epithelial cells enhance tumorigenicity: Cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT. Int. J. Cancer, 122(7), 1483-1495. https://doi.org/10.1002/ijc.23222 Bhojwani, D. y Pui, C. H. (2013). Relapsed childhood acute lymphoblastic leukaemia. En Lancet Oncol. https://doi.org/10.1016/S1470-2045(12)70580-6 Blaser, H., Dostert, C., Mak, T. W., y Brenner, D. (2016). TNF and ROS Crosstalk in Inflammation. En Trends in Cell Biology (Vol. 26, Número 4). https://doi.org/10.1016/j.tcb.2015.12.002 Bonilla, X., Vanegas, N.-D. P., y Vernot, J. P. (2019). Acute Leukemia Induces Senescence and Impaired Osteogenic Differentiation in Mesenchymal Stem Cells Endowing Leukemic Cells with Functional Advantages. Stem Cells Int, 2019, 1-16. https://doi.org/10.1155/2019/3864948 Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., y Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J. Clin., 68(6), 394-424. https://doi.org/10.3322/caac.21492 Brenner, A. K., Reikvam, H., y Bruserud, Ø. (2016). A Subset of Patients with Acute Myeloid Leukemia Has Leukemia Cells Characterized by Chemokine Responsiveness and Altered Expression of Transcriptional as well as Angiogenic Regulators. Front Immunol, 7(MAY). https://doi.org/10.3389/fimmu.2016.00205 Brücher, B. L. D. M. y Jamall, I. S. (2014). Cell-cell communication in the tumor microenvironment, carcinogenesis, and anticancer treatment. En Cellular Physiology and Biochemistry (Vol. 34, Número 2). https://doi.org/10.1159/000362978 Burger, J. A., Tsukada, N., Burger, M., Zvaifler, N. J., Dell’Aquila, M., y Kipps, T. J. (2000). Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell–derived factor-1. Blood, 96(8), 2655-2663. https://doi.org/10.1182/blood.V96.8.2655 Canli, Ö., Nicolas, A. M., Gupta, J., Finkelmeier, F., Goncharova, O., Pesic, M., Neumann, T., Horst, D., Löwer, M., Sahin, U., y Greten, F. R. (2017). Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis. Cancer Cell, 32(6). https://doi.org/10.1016/j.ccell.2017.11.004 Chauhan, D., Uchiyama, H., Akbarali, Y., Urashima, M., Yamamoto, K., Libermann, T., y Anderson, K. (1996). Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood, 87(3), 1104-1112. https://doi.org/10.1182/blood.V87.3.1104.bloodjournal8731104 Chen, X., Li, N., Weng, J., y Du, X. (2021). Senescent Mesenchymal Stem Cells in Myelodysplastic Syndrome: Functional Alterations, Molecular Mechanisms, and Therapeutic Strategies. En Frontiers in Cell and Developmental Biology (Vol. 8). https://doi.org/10.3389/fcell.2020.617466 Cheung, L. C., Tickner, J., Hughes, A. M., Skut, P., Howlett, M., Foley, B., Oommen, J., Wells, J. E., He, B., Singh, S., Chua, G.-A., Ford, J., Mullighan, C. G., Kotecha, R. S., y Kees, U. R. (2018). New therapeutic opportunities from dissecting the pre-B leukemia bone marrow microenvironment. Leukemia, 32(11), 2326-2338. https://doi.org/10.1038/s41375-018-0144-7 Childs, B. G., Baker, D. J., Kirkland, J. L., Campisi, J., y Deursen, J. M. (2014). Senescence and apoptosis: dueling or complementary cell fates? EMBO reports. https://doi.org/10.15252/embr.201439245 Cidado, J., Wong, H. Y., Marc Rosen, D., Cimino-Mathews, A., Garay, J. P., Fessler, A. G., Rasheed, Z. A., Hicks, J., Cochran, R. L., Croessmann, S., Zabransky, D. J., Mohseni, M., Beaver, J. A., Chu, D., Cravero, K., Christenson, E. S., Medford, A., Mattox, A., De Marzo, A. M., … Park, B. H. (2016). Ki-67 is required for maintenance of cancer stem cells but not cell proliferation. Oncotarget. https://doi.org/10.18632/oncotarget.7057 Cimmino, A., Calin, G. A., Fabbri, M., Iorio, M. V., Ferracin, M., Shimizu, M., Wojcik, S. E., Aqeilan, R. I., Zupo, S., Dono, M., Rassenti, L., Alder, H., Volinia, S., Liu, C. -g., Kipps, T. J., Negrini, M., y Croce, C. M. (2005). miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl. Acad. Sci. U.S.A., 102(39), 13944-13949. https://doi.org/10.1073/pnas.0506654102 Conforti, A., Biagini, S., Del Bufalo, F., Sirleto, P., Angioni, A., Starc, N., Li Pira, G., Moretta, F., Proia, A., Contoli, B., Genovese, S., Ciardi, C., Avanzini, M. A., Rosti, V., Lo-Coco, F., Locatelli, F., y Bernardo, M. E. (2013). Biological, Functional and Genetic Characterization of Bone Marrow-Derived Mesenchymal Stromal Cells from Pediatric Patients Affected by Acute Lymphoblastic Leukemia. PLoS ONE, 8(11), e76989. https://doi.org/10.1371/journal.pone.0076989 Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P. Y., y Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. https://doi.org/10.1371/journal.pbio.0060301 Corradi, G., Baldazzi, C., Očadlíková, D., Marconi, G., Parisi, S., Testoni, N., Finelli, C., Cavo, M., Curti, A., y Ciciarello, M. (2018). Mesenchymal stromal cells from myelodysplastic and acute myeloid leukemia patients display in vitro reduced proliferative potential and similar capacity to support leukemia cell survival. Stem Cell Res. Ther., 9(1), 271. https://doi.org/10.1186/s13287-018-1013-z Corre, J., Mahtouk, K., Attal, M., Gadelorge, M., Huynh, A., Fleury-Cappellesso, S., Danho, C., Laharrague, P., Klein, B., Rème, T., y Bourin, P. (2007). Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia, 21(5), 1079-1088. https://doi.org/10.1038/sj.leu.2404621 Cosentino-Gomes, D., Rocco-Machado, N., y Meyer-Fernandes, J. R. (2012). Cell Signaling through Protein Kinase C Oxidation and Activation. Int. J. Mol. Sci., 13(9), 10697-10721. https://doi.org/10.3390/ijms130910697 DANE. (2018). Defunciones Estadísticas Vitales. http://systema74.dane.gov.co/bincol/RpWebEngine.exe/Portal?BASE=DEFOC08&lang=esp Darwish, N. H. E., Sudha, T., Godugu, K., Bharali, D. J., Elbaz, O., El-ghaffar, H. A. A., Azmy, E., Anber, N., y Mousa, S. A. (2019). Novel Targeted Nano-Parthenolide Molecule against NF-kB in Acute Myeloid Leukemia. Molecules, 24(11), 2103. https://doi.org/10.3390/molecules24112103 Davalli, P., Mitic, T., Caporali, A., Lauriola, A., y D’Arca, D. (2016). ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases. Oxid. Med. Cell. Longev., 2016, 1-18. https://doi.org/10.1155/2016/3565127 de Vasconcellos, J. F., Laranjeira, A. B. A., Zanchin, N. I. T., Otubo, R., Vaz, T. H., Cardoso, A. A., Brandalise, S. R., y Yunes, J. A. (2011). Increased CCL2 and IL-8 in the bone marrow microenvironment in acute lymphoblastic leukemia. Pediatr. Blood Cancer, 56(4), 568-577. https://doi.org/10.1002/pbc.22941 Den Boer, M. L., van Slegtenhorst, M., De Menezes, R. X., Cheok, M. H., Buijs-Gladdines, J. G., Peters, S. T., Van Zutven, L. J., Beverloo, H. B., Van der Spek, P. J., Escherich, G., Horstmann, M. A., Janka-Schaub, G. E., Kamps, W. A., Evans, W. E., y Pieters, R. (2009). A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. https://doi.org/10.1016/S1470-2045(08)70339-5 Denizot, Y., Fixe, P., Liozon, E., y Praloran, V. (1996). Serum interleukin-8 (IL-8) and IL-6 concentrations in patients with hematologic malignancies [letter]. Blood, 87(9), 4016-4017. https://doi.org/10.1182/blood.V87.9.4016.bloodjournal8794016 Dierks, C., Grbic, J., Zirlik, K., Beigi, R., Englund, N. P., Guo, G.-R., Veelken, H., Engelhardt, M., Mertelsmann, R., Kelleher, J. F., Schultz, P., y Warmuth, M. (2007). Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med, 13(8), 944-951. https://doi.org/10.1038/nm1614 Ding, W., Nowakowski, G. S., Knox, T. R., Boysen, J. C., Maas, M. L., Schwager, S. M., Wu, W., Wellik, L. E., Dietz, A. B., Ghosh, A. K., Secreto, C. R., Medina, K. L., Shanafelt, T. D., Zent, C. S., Call, T. G., y Kay, N. E. (2009). Bi-directional activation between mesenchymal stem cells and CLL B-cells: implication for CLL disease progression. Br. J. Haematol., 147(4), 471-483. https://doi.org/10.1111/j.1365-2141.2009.07868.x Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F. ., Krause, D. S., Deans, R. J., Keating, A., Prockop, D. J., y Horwitz, E. M. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8(4), 315-317. https://doi.org/10.1080/14653240600855905 Duarte, D., Hawkins, E. D., y Lo Celso, C. (2018). The interplay of leukemia cells and the bone marrow microenvironment. En Blood (Vol. 131, Número 14). https://doi.org/10.1182/blood-2017-12-784132 Ebinger, S., Özdemir, E. Z., Ziegenhain, C., Tiedt, S., Castro Alves, C., Grunert, M., Dworzak, M., Lutz, C., Turati, V. A., Enver, T., Horny, H.-P., Sotlar, K., Parekh, S., Spiekermann, K., Hiddemann, W., Schepers, A., Polzer, B., Kirsch, S., Hoffmann, M., … Jeremias, I. (2016). Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia. Cancer Cell, 30(6), 849-862. https://doi.org/10.1016/j.ccell.2016.11.002 Egle, A., Holler, C., Pinon, J. D., Denk, U., Heyder, C., y Greil, R. (2008). PKCβ Is Essential for the Development of CLL in the TCL1 Transgenic Mouse Model: Validation of PKCβ as a Therapeutic Target in CLL. Blood, 112(11), 4164-4164. https://doi.org/10.1182/blood.V112.11.4164.4164 El-Gamal, D., Williams, K., LaFollette, T. D., Cannon, M., Blachly, J. S., Zhong, Y., Woyach, J. A., Williams, E., Awan, F. T., Jones, J., Andritsos, L., Maddocks, K., Wu, C.-H., Chen, C.-S., Lehman, A., Zhang, X., Lapalombella, R., y Byrd, J. C. (2014). PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL. Blood, 124(9), 1481-1491. https://doi.org/10.1182/blood-2014-05-574830 Garderet, L., Mazurier, C., Chapel, A., Ernou, I., Boutin, L., Holy, X., Gorin, N. C., Lopez, M., Doucet, C., y Lataillade, J.-J. (2007). Mesenchymal stem cell abnormalities in patients with multiple myeloma. Leukemia & Lymphoma, 48(10), 2032-2041. https://doi.org/10.1080/10428190701593644 Gill, J. G., Piskounova, E., y Morrison, S. J. (2016). Cancer, oxidative stress, and metastasis. Cold Spring Harbor Symposia on Quantitative Biology, 81(1). https://doi.org/10.1101/sqb.2016.81.030791 Giordano, P., Molinari, A. C., Del Vecchio, G. C., Saracco, P., Russo, G., Altomare, M., Perutelli, P., Crescenzio, N., Santoro, N., Marchetti, M., De Mattia, D., y Falanga, A. (2010). Prospective study of hemostatic alterations in children with acute lymphoblastic leukemia. Am. J. Hematol., 85(5), NA-NA. https://doi.org/10.1002/ajh.21665 Gnani, D., Crippa, S., della Volpe, L., Rossella, V., Conti, A., Lettera, E., Rivis, S., Ometti, M., Fraschini, G., Bernardo, M. E., y Di Micco, R. (2019). An early‐senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro‐inflammatory program. Aging Cell, 18(3), e12933. https://doi.org/10.1111/acel.12933 Gopalakrishna, R. y Jaken, S. (2000). Protein kinase C signaling and oxidative stress. Free Radic. Biol. Med., 28(9), 1349-1361. https://doi.org/10.1016/S0891-5849(00)00221-5 Grivennikov, S. I., Greten, F. R., y Karin, M. (2010). Immunity, Inflammation, and Cancer. En Cell (Vol. 140, Número 6). https://doi.org/10.1016/j.cell.2010.01.025 Guo, J., Zhao, Y., Fei, C., Zhao, S., Zheng, Q., Su, J., Wu, D., Li, X., y Chang, C. (2018). Dicer1 downregulation by multiple myeloma cells promotes the senescence and tumor-supporting capacity and decreases the differentiation potential of mesenchymal stem cells. Cell Death Dis, 9(5), 512. https://doi.org/10.1038/s41419-018-0545-6 Gupta, V. A., Matulis, S. M., Conage-Pough, J. E., Nooka, A. K., Kaufman, J. L., Lonial, S., y Boise, L. H. (2017). Bone marrow microenvironment–derived signals induce Mcl-1 dependence in multiple myeloma. Blood, 129(14), 1969-1979. https://doi.org/10.1182/blood-2016-10-745059 Halton, J. M., Atkinson, S. A., Fraher, L., Webber, C. E., Cockshott, W. P., Tam, C., y Barr, R. D. (1995). Mineral homeostasis and bone mass at diagnosis in children with acute lymphoblastic leukemia. J Pediatr, 126(4), 557-564. https://doi.org/10.1016/S0022-3476(95)70349-7 Hamidi, H. y Ivaska, J. (2018). Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer., 18(9), 533-548. https://doi.org/10.1038/s41568-018-0038-z Hartl, D., Latzin, P., Hordijk, P., Marcos, V., Rudolph, C., Woischnik, M., Krauss-Etschmann, S., Koller, B., Reinhardt, D., Roscher, A. A., Roos, D., y Griese, M. (2007). Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat. Med., 13(12), 1423-1430. https://doi.org/10.1038/nm1690 Hayden, M. S. y Ghosh, S. (2008). Shared Principles in NF-κB Signaling. Cell, 132(3), 344-362. https://doi.org/10.1016/j.cell.2008.01.020 Hellmich, C., Moore, J. A., Bowles, K. M., y Rushworth, S. A. (2020). Bone Marrow Senescence and the Microenvironment of Hematological Malignancies. En Frontiers in Oncology (Vol. 10). https://doi.org/10.3389/fonc.2020.00230 Ho, A. D., Wagner, W., y Franke, W. (2008). Heterogeneity of mesenchymal stromal cell preparations. Cytotherapy, 10(4), 320-330. https://doi.org/10.1080/14653240802217011 Houghten, R. A. (1985). General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids. Proc. Natl. Acad. Sci. U.S.A, 82(15), 5131-5135. https://doi.org/10.1073/pnas.82.15.5131 Hu, D., Yuan, S., Zhong, J., Liu, Z., Wang, Y., Liu, L., Li, J., Wen, F., Liu, J., y Zhang, J. (2021). Cellular senescence and hematological malignancies: From pathogenesis to therapeutics. En Pharmacology and Hunger, S. P. y Mullighan, C. G. (2015). Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine. Blood, 125(26), 3977-3987. https://doi.org/10.1182/blood-2015-02-580043 Iannetti, A., Ledoux, A. C., Tudhope, S. J., Sellier, H., Zhao, B., Mowla, S., Moore, A., Hummerich, H., Gewurz, B. E., Cockell, S. J., Jat, P. S., Willmore, E., y Perkins, N. D. (2014). Regulation of p53 and Rb Links the Alternative NF-κB Pathway to EZH2 Expression and Cell Senescence. PLoS Genetics, 10(9). https://doi.org/10.1371/journal.pgen.1004642 Imbert, V. y Peyron, J.-F. (2017). NF-κB in Hematological Malignancies. Biomedicines, 5(4), 27. https://doi.org/10.3390/biomedicines5020027 Ioanou, K., Cheng, K. F., Crichlow, G. V., Birmpilis, A. I., Lolis, E. J., Tsitsilonis, O. E., y Al-Abed, Y. (2014). ISO-66, a novel inhibitor of macrophage migration inhibitory factor, shows efficacy in melanoma and colon cancer models. International Journal of Oncology, 45(4). https://doi.org/10.3892/ijo.2014.2551 Iwamoto, S., Mihara, K., Downing, J. R., Pui, C.-H., y Campana, D. (2007). Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. J Clin Invest, 117(4), 1049-1057. https://doi.org/10.1172/JCI30235 Izadpanah, R., Kaushal, D., Kriedt, C., Tsien, F., Patel, B., Dufour, J., y Bunnell, B. A. (2008). Long-term In vitro Expansion Alters the Biology of Adult Mesenchymal Stem Cells. Cancer Res., 68(11), 4229-4238. https://doi.org/10.1158/0008-5472.CAN-07-5272 Jacamo, R., Chen, Y., Wang, Z., Ma, W., Zhang, M., Spaeth, E. L., Wang, Y., Battula, V. L., Mak, P. Y., Schallmoser, K., Ruvolo, P., Schober, W. D., Shpall, E. J., Nguyen, M. H., Strunk, D., Bueso-Ramos, C. E., Konoplev, S., Davis, R. E., Konopleva, M., y Andreeff, M. (2014). Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance. Blood, 123(17), 2691-2702. https://doi.org/10.1182/blood-2013-06-511527 Jiffar, T., Kurinna, S., Suck, G., Carlson-Bremer, D., Ricciardi, M. R., Konopleva, M., Andreeff, M., y Ruvolo, P. P. (2004). PKC α mediates chemoresistance in acute lymphoblastic leukemia through effects on Bcl2 phosphorylation. Leukemia. https://doi.org/10.1038/sj.leu.2403275 Jin, H. J., Lee, H. J., Heo, J., Lim, J., Kim, M., Kim, M. K., Nam, H. Y., Hong, G. H., Cho, Y. S., Choi, S. J., Kim, I. G., Shin, D. M., y Kim, S. W. (2016). Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells. Antioxidants and Redox Signaling. https://doi.org/10.1089/ars.2015.6359 Jin, X.-T., Chen, M.-L., Li, R.-J., An, Q., Song, L., Zhao, Y., Xiao, H., Cheng, L., y Li, Z.-Y. (2016). Progression and inflammation of human myeloid leukemia induced by ambient PM2.5 exposure. Arch. Toxicol, 90(8), 1929-1938. https://doi.org/10.1007/s00204-015-1610-x Johmura, Y. y Nakanishi, M. (2016). Multiple facets of p53 in senescence induction and maintenance. Cancer Sci., 107(11), 1550-1555. https://doi.org/10.1111/cas.13060 Johnson, S. M., Dempsey, C., Chadwick, A., Harrison, S., Liu, J., Di, Y., McGinn, O. J., Fiorillo, M., Sotgia, F., Lisanti, M. P., Parihar, M., Krishnan, S., y Saha, V. (2016). Metabolic reprogramming of bone marrow stromal cells by leukemic extracellular vesicles in acute lymphoblastic leukemia. Blood, 128(3), 453-456. https://doi.org/10.1182/blood-2015-12-688051 Joyce, D., Albanese, C., Steer, J., Fu, M., Bouzahzah, B., y Pestell, R. G. (2001). NF-κB and cell-cycle regulation: The cyclin connection. En Cytokine Growth Factor Rev. https://doi.org/10.1016/S1359-6101(00)00018-6 Juneja, H. S., Schmalsteig, F. C., Lee, S., y Chen, J. (1993). Vascular cell adhesion molecule-1 and VLA-4 are obligatory adhesion proteins in the heterotypic adherence between human leukemia/lymphoma cells and marrow stromal cells. Experimental Hematology, 21(3). Karin, M. (2006). Nuclear factor-κB in cancer development and progression. Nature, 441(7092), 431-436. https://doi.org/10.1038/nature04870 Keenan, C., Thompson, S., Knox, K., y Pears, C. (1999). Protein Kinase C-α Is Essential for Ramos-BL B Cell Survival. Cell. Immunol., 196(2), 104-109. https://doi.org/10.1006/cimm.1999.1549 Kfoury, Y. y Scadden, D. T. (2015). Mesenchymal Cell Contributions to the Stem Cell Niche. Cell Stem Cell, 16(3), 239-253. https://doi.org/10.1016/j.stem.2015.02.019 Kim, J.-A., Shim, J.-S., Lee, G.-Y., Yim, H. W., Kim, T.-M., Kim, M., Leem, S.-H., Lee, J.-W., Min, C.-K., y Oh, I.-H. (2015). Microenvironmental Remodeling as a Parameter and Prognostic Factor of Heterogeneous Leukemogenesis in Acute Myelogenous Leukemia. Cancer Res, 75(11), 2222-2231. https://doi.org/10.1158/0008-5472.CAN-14-3379 Kim, J.-H., Lee, H.-S., Choi, H.-K., Kim, J.-A., Chu, I.-S., Leem, S.-H., y Oh, I.-H. (2016). Heterogeneous Niche Activity of Ex-Vivo Expanded MSCs as Factor for Variable Outcomes in Hematopoietic Recovery. PLOS ONE, 11(12), e0168036. https://doi.org/10.1371/journal.pone.0168036 Kleppe, M., Koche, R., Zou, L., van Galen, P., Hill, C. E., Dong, L., De Groote, S., Papalexi, E., Hanasoge Somasundara, A. V., Cordner, K., Keller, M., Farnoud, N., Medina, J., McGovern, E., Reyes, J., Roberts, J., Witkin, M., Rapaport, F., Teruya-Feldstein, J., … Levine, R. L. (2018). Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell, 33(1), 29-43.e7. https://doi.org/10.1016/j.ccell.2017.11.009 Klopp, A. H., Gupta, A., Spaeth, E., Andreeff, M., y Marini, F. (2011). Concise Review: Dissecting a Discrepancy in the Literature: Do Mesenchymal Stem Cells Support or Suppress Tumor Growth? STEM CELLS, 29(1), 11-19. https://doi.org/10.1002/stem.559 Konopleva, M., Konoplev, S., Hu, W., Zaritskey, A., Afanasiev, B., y Andreeff, M. (2002). Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia, 16(9), 1713-1724. https://doi.org/10.1038/sj.leu.2402608 Krevvata, M., Silva, B. C., Manavalan, J. S., Galan-Diez, M., Kode, A., Matthews, B. G., Park, D., Zhang, C. A., Galili, N., Nickolas, T. L., Dempster, D. W., Dougall, W., Teruya-Feldstein, J., Economides, A. N., Kalajzic, I., Raza, A., Berman, E., Mukherjee, S., Bhagat, G., y Kousteni, S. (2014). Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood, 124(18). https://doi.org/10.1182/blood-2013-07-517219 Krtolica, A., Parrinello, S., Lockett, S., Desprez, P.-Y., y Campisi, J. (2001). Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging. Proc Natl Acad Sci U S A, 98(21), 12072-12077. https://doi.org/10.1073/pnas.211053698 Kumar, A., Anand, T., Bhattacharyya, J., Sharma, A., y Jaganathan, B. G. (2018). K562 chronic myeloid leukemia cells modify osteogenic differentiation and gene expression of bone marrow stromal cells. J Cell Commun Signal, 12(2), 441-450. https://doi.org/10.1007/s12079-017-0412-8 Kurtova, A. V., Balakrishnan, K., Chen, R., Ding, W., Schnabl, S., Quiroga, M. P., Sivina, M., Wierda, W. G., Estrov, Z., Keating, M. J., Shehata, M., Jäger, U., Gandhi, V., Kay, N. E., Plunkett, W., y Burger, J. A. (2009). Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood, 114(20), 4441-4450. https://doi.org/10.1182/blood-2009-07-233718 Lagneaux, L., Delforge, A., Bron, D., De Bruyn, C., y Stryckmans, P. (1998). Chronic Lymphocytic Leukemic B Cells But Not Normal B Cells Are Rescued From Apoptosis by Contact With Normal Bone Marrow Stromal Cells. Blood, 91(7), 2387-2396. https://doi.org/10.1182/blood.V91.7.2387.2387_2387_2396 Lašťovička, J., Rataj, M., y Bartůňková, J. (2016). Assessment of lymphocyte proliferation for diagnostic purpose: Comparison of CFSE staining, Ki-67 expression and 3H-thymidine incorporation. Human Immunology. https://doi.org/10.1016/j.humimm.2016.08.012 Lawrence, T. (2009). The Nuclear Factor NF- B Pathway in Inflammation. Cold Spring Harb. Perspect. Biol., 1(6), a001651-a001651. https://doi.org/10.1101/cshperspect.a001651 Lee, G.-Y., Jeong, S.-Y., Lee, H.-R., y Oh, I.-H. (2019). Age-related differences in the bone marrow stem cell niche generate specialized microenvironments for the distinct regulation of normal hematopoietic and leukemia stem cells. Sci Rep, 9(1), 1007. https://doi.org/10.1038/s41598-018-36999-5 Lemmon, M. A. y Schlessinger, J. (2010). Cell Signaling by Receptor Tyrosine Kinases. Cell, 141(7), 1117-1134. https://doi.org/10.1016/j.cell.2010.06.011 Lerrer, S., Liubomirski, Y., Bott, A., Abnaof, K., Oren, N., Yousaf, A., Körner, C., Meshel, T., Wiemann, S., y Ben-Baruch, A. (2017). Co-Inflammatory Roles of TGFβ1 in the Presence of TNFα Drive a Pro-inflammatory Fate in Mesenchymal Stem Cells. Front Immunol, 8, 479. https://doi.org/10.3389/fimmu.2017.00479 Lim, M., Pang, Y., Ma, S., Hao, S., Shi, H., Zheng, Y., Hua, C., Gu, X., Yang, F., Yuan, W., y Cheng, T. (2016). Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow. Leukemia, 30(1), 154-162. https://doi.org/10.1038/leu.2015.210 Liu, W. . y Heckman, C. . (1998). The Sevenfold Way of PKC Regulation. Cell. Signal., 10(8), 529-542. https://doi.org/10.1016/S0898-6568(98)00012-6 Loi, T. H., Dai, P., Carlin, S., Melo, J. V, y Ma, D. D. F. (2016). Pro-survival role of protein kinase C epsilon in Philadelphia chromosome positive acute leukemia. Leuk. Lymphoma, 57(2), 411-418. https://doi.org/10.3109/10428194.2015.1043545 Lutzny, G., Kocher, T., Schmidt-Supprian, M., Rudelius, M., Klein-Hitpass, L., Finch, A. J., Dürig, J., Wagner, M., Haferlach, C., Kohlmann, A., Schnittger, S., Seifert, M., Wanninger, S., Zaborsky, N., Oostendorp, R., Ruland, J., Leitges, M., Kuhnt, T., Schäfer, Y., … Ringshausen, I. (2013). Protein Kinase C-β-Dependent Activation of NF-κB in Stromal Cells Is Indispensable for the Survival of Chronic Lymphocytic Leukemia B Cells In Vivo. Cancer Cell, 23(1), 77-92. https://doi.org/10.1016/j.ccr.2012.12.003 Lwin, T., Hazlehurst, L. A., Li, Z., Dessureault, S., Sotomayor, E., Moscinski, L. C., Dalton, W. S., y Tao, J. (2007). Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-κB (RelB/p52) in non-Hodgkin’s lymphoma cells. Leukemia, 21(7), 1521-1531. https://doi.org/10.1038/sj.leu.2404723 Macanas-Pirard, P., Quezada, T., Navarrete, L., Broekhuizen, R., Leisewitz, A., Nervi, B., y Ramírez, P. A. (2017). The CCL2/CCR2 axis affects transmigration and proliferation but not resistance to chemotherapy of acute myeloid leukemia cells. PLoS ONE, 12(1). https://doi.org/10.1371/journal.pone.0168888 Macip, S., Igarashi, M., Berggren, P., Yu, J., Lee, S. W., y Aaronson, S. A. (2003). Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol. Cell. Biol. https://doi.org/10.1128/MCB.23.23.8576-8585.2003 Mahindra, A., Hideshima, T., y Anderson, K. C. (2010). Multiple myeloma: Biology of the disease. En Blood Reviews (Vol. 24, Número SUPPL. 1). https://doi.org/10.1016/S0268-960X(10)70003-5 Manabe, A., Coustan-Smith, E., Behm, F. G., Raimondi, S. C., y Campana, D. (1992). Bone marrow-derived stromal cells prevent apoptotic cell death in B-lineage acute lymphoblastic leukemia. Blood, 79(9), 2370-2377. http://www.ncbi.nlm.nih.gov/pubmed/1373973 Manabe, A., Murti, K., Coustan-Smith, E., Kumagai, M., Behm, F., Raimondi, S., y Campana, D. (1994). Adhesion-dependent survival of normal and leukemic human B lymphoblasts on bone marrow stromal cells. Blood, 83(3), 758-766. https://doi.org/10.1182/blood.V83.3.758.bloodjournal833758 Mangolini, M., Götte, F., Moore, A., Ammon, T., Oelsner, M., Lutzny-Geier, G., Klein-Hitpass, L., Williamson, J. C., Lehner, P. J., Dürig, J., Möllmann, M., Rásó-Barnett, L., Hughes, K., Santoro, A., Méndez-Ferrer, S., Oostendorp, R. A. J., Zimber-Strobl, U., Peschel, C., Hodson, D. J., … Ringshausen, I. (2018). Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia. Nat. Commun., 9(1), 3839. https://doi.org/10.1038/s41467-018-06069-5 Mangolini, M. y Ringshausen, I. (2020). Bone Marrow Stromal Cells Drive Key Hallmarks of B Cell Malignancies. Int. J. Mol. Sci., 21(4), 1466. https://doi.org/10.3390/ijms21041466 Marlein, C. R., Piddock, R. E., Mistry, J. J., Zaitseva, L., Hellmich, C., Horton, R. H., Zhou, Z., Auger, M. J., Bowles, K. M., y Rushworth, S. A. (2019). CD38-Driven Mitochondrial Trafficking Promotes Bioenergetic Plasticity in Multiple Myeloma. Cancer Research, 79(9), 2285-2297. https://doi.org/10.1158/0008-5472.CAN-18-0773 Mas-Bargues, C., Sanz-Ros, J., Román-Domínguez, A., Inglés, M., Gimeno-Mallench, L., El Alami, M., Viña-Almunia, J., Gambini, J., Viña, J., y Borrás, C. (2019). Relevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine. Int. J. Mol. Sci., 20(5), 1195. https://doi.org/10.3390/ijms20051195 Medina, D. J., Goodell, L., Glod, J., Gelinas, C., Rabson, A. B., y Strair, R. K. (2012). Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor B pathways. Haematologica, 97(8), 1255-1263. https://doi.org/10.3324/haematol.2011.040659 Meggio, F., Deana, A. D., Ruzzene, M., Brunati, A. M., Cesaro, L., Guerra, B., Meyer, T., Mett, H., Fabbro, D., Furet, P., Dobrowolska, G., y Pinna, L. A. (1995). Different Susceptibility of Protein Kinases to Staurosporine Inhibition: Kinetic Studies and Molecular Bases for the Resistance of Protein Kinase CK2. Eur. j. biochem., 234(1). https://doi.org/10.1111/j.1432-1033.1995.317_c.x Minsalud y Colciencias. (2013). Guía de Práctica Clínica para la detección oportuna, diagnóstico y seguimiento de leucemia linfoide aguda y leucemia mieloide aguda en niños, niñas y adolescentes. En Centro Nacional de Investigacion en Evidencia y Tecnologia en Salud CINETS (Número 9). Miranda-Filho, A., Piñeros, M., Ferlay, J., Soerjomataram, I., Monnereau, A., y Bray, F. (2018). Epidemiological patterns of leukaemia in 184 countries: a population-based study. Lancet Haematol., 5(1), e14-e24. https://doi.org/10.1016/S2352-3026(17)30232-6 Möricke, A., Reiter, A., Zimmermann, M., Gadner, H., Stanulla, M., Dördelmann, M., Löning, L., Beier, R., Ludwig, W. D., Ratei, R., Harbott, J., Boos, J., Mann, G., Niggli, F., Feldges, A., Henze, G., Welte, K., Beck, J. D., Klingebiel, T., … Schrappe, M. (2008). Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: Treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood, 111(9). https://doi.org/10.1182/blood-2007-09-112920 Mullighan, C. G. (2013). Genomic Characterization of Childhood Acute Lymphoblastic Leukemia. Sem Hematol, 50(4), 314-324. https://doi.org/10.1053/j.seminhematol.2013.10.001 Muto, T., Walker, C. S., Choi, K., Hueneman, K., Smith, M. A., Gul, Z., Garcia-Manero, G., Ma, A., Zheng, Y., y Starczynowski, D. T. (2020). Adaptive response to inflammation contributes to sustained myelopoiesis and confers a competitive advantage in myelodysplastic syndrome HSCs. Nat. Immunol., 21(5), 535-545. https://doi.org/10.1038/s41590-020-0663-z Nakagawa, R., Soh, J. W., y Michie, A. M. (2006). Subversion of protein kinase Cα signaling in hematopoietic progenitor cells results in the generation of a B-cell chronic lymphocytic leukemia-like population in vivo. Cancer Research, 66(1). https://doi.org/10.1158/0008-5472.CAN-05-0841 Nakagawa, R., Vukovic, M., Tarafdar, A., Cosimo, E., Dunn, K., McCaig, A. M., Holroyd, A., McClanahan, F., Ramsay, A. G., Gribben, J. G., y Michie, A. M. (2015). Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKCα subversion induces up-regulation of PKCβII expression in B lymphocytes. Haematologica, 100(4). https://doi.org/10.3324/haematol.2014.112276 Nomellini, V., Brubaker, A. L., Mahbub, S., Palmer, J. L., Gomez, C. R., y Kovacs, E. J. (2012). Dysregulation of neutrophil CXCR2 and pulmonary endothelial ICAM-1 promotes age-related pulmonary inflammation. Aging Dis., 3(3). Oh, I.-H., Jeong, S.-Y., y Kim, J.-A. (2019). Normal and leukemic stem cell niche interactions. Curr Opin Hematol, 26(4), 249-257. https://doi.org/10.1097/MOH.0000000000000508 Oliver, L., Hue, E., Séry, Q., Lafargue, A., Pecqueur, C., Paris, F., y Vallette, F. M. (2013). Differentiation-Related Response to DNA Breaks in Human Mesenchymal Stem Cells. Stem Cells, 31(4), 800-807. https://doi.org/10.1002/stem.1336 Ortiz-Montero, P., Londoño-Vallejo, A., y Vernot, J.-P. (2017). Senescence-associated IL-6 and IL-8 cytokines induce a self- and cross-reinforced senescence/inflammatory milieu strengthening tumorigenic capabilities in the MCF-7 breast cancer cell line. Cell Commun Signal., 15(1), 17. https://doi.org/10.1186/s12964-017-0172-3 Paggetti, J., Haderk, F., Seiffert, M., Janji, B., Distler, U., Ammerlaan, W., Kim, Y. J., Adam, J., Lichter, P., Solary, E., Berchem, G., y Moussay, E. (2015). Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. Blood, 126(9), 1106-1117. https://doi.org/10.1182/blood-2014-12-618025 Pardo, C. y Cendales, R. (2015). Incidencia, mortalidad y prevalencia de cáncer en Colombia, 2007-2011. Primera edición. Bogotá. D.C. Instituto Nacional de Cancerología (Vol. 1). Park, E., Chen, J., Moore, A., Mangolini, M., Santoro, A., Boyd, J. R., Schjerven, H., Ecker, V., Buchner, M., Williamson, J. C., Lehner, P. J., Gasparoli, L., Williams, O., Bloehdorn, J., Stilgenbauer, S., Leitges, M., Egle, A., Schmidt-Supprian, M., Frietze, S., y Ringshausen, I. (2020). Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance. Sci. Transl. Med., 12(526), eaax9340. https://doi.org/10.1126/scitranslmed.aax9340 Patel, V., Chen, L. S., Wierda, W. G., Balakrishnan, K., y Gandhi, V. (2014). Impact of bone marrow stromal cells on Bcl-2 family members in chronic lymphocytic leukemia. Leuk. Lymphoma, 55(4). https://doi.org/10.3109/10428194.2013.819573 Peled, A., Klein, S., Beider, K., Burger, J. A., y Abraham, M. (2018). Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies. Cytokine, 109, 11-16. https://doi.org/10.1016/j.cyto.2018.02.020 Perdomo-Arciniegas, A. M., Patarroyo, M. E., y Vernot, J.-P. (2008). Novel Chimeric Peptide Inhibits Protein Kinase C and Induces Apoptosis in Human Immune Cells. Int J Pept Res Ther., 14(1), 64-74. https://doi.org/10.1007/s10989-007-9118-8 Pietras, K. y Östman, A. (2010). Hallmarks of cancer: Interactions with the tumor stroma. Exp. Cell Res., 316(8), 1324-1331. https://doi.org/10.1016/j.yexcr.2010.02.045 Pleyer, L., Valent, P., y Greil, R. (2016). Mesenchymal stem and progenitor cells in normal and dysplastic hematopoiesis—Masters of survival and clonality? En International Journal of Molecular Sciences (Vol. 17, Número 7). https://doi.org/10.3390/ijms17071009 Polak, R., de Rooij, B., Pieters, R., y den Boer, M. L. (2015). B-cell precursor acute lymphoblastic leukemia cells use tunneling nanotubes to orchestrate their microenvironment. Blood, 126(21), 2404-2414. https://doi.org/10.1182/blood-2015-03-634238 Pui, C.-H. y Evans, W. E. (2006). Treatment of Acute Lymphoblastic Leukemia. N Engl J Med, 354(2), 166-178. https://doi.org/10.1056/NEJMra052603 Quintarelli, C., De Angelis, B., Errichiello, S., Caruso, S., Esposito, N., Colavita, I., Raia, M., Pagliuca, S., Pugliese, N., Risitano, A. M., Picardi, M., Luciano, L., Saglio, G., Martinelli, G., y Pane, F. (2014). Selective strong synergism of Ruxolitinib and second generation tyrosine kinase inhibitors to overcome bone marrow stroma related drug resistance in chronic myelogenous leukemia. Leuk. Res., 38(2), 236-242. https://doi.org/10.1016/j.leukres.2013.11.006 Raaijmakers, M. H. G. P., Mukherjee, S., Guo, S., Zhang, S., Kobayashi, T., Schoonmaker, J. A., Ebert, B. L., Al-Shahrour, F., Hasserjian, R. P., Scadden, E. O., Aung, Z., Matza, M., Merkenschlager, M., Lin, C., Rommens, J. M., y Scadden, D. T. (2010). Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature, 464(7290), 852-857. https://doi.org/10.1038/nature08851 Raffaghello, L., Vacca, A., Pistoia, V., y Ribatti, D. (2015). Cancer associated fibroblasts in hematological malignancies. Oncotarget, 6(5), 2589-2603. https://doi.org/10.18632/oncotarget.2661 Raposo, G. y Stoorvogel, W. (2013). Extracellular vesicles: Exosomes, microvesicles, and friends. Int. J. Cell Biol., 200(4), 373-383. https://doi.org/10.1083/jcb.201211138 Redig, A. J. y Platanias, L. C. (2008). Protein kinase C signalling in leukemia. Leukemia & Lymphoma, 49(7), 1255-1262. https://doi.org/10.1080/10428190802007726 Reikvam, H., Brenner, A. K., Hagen, K. M., Liseth, K., Skrede, S., Hatfield, K. J., y Bruserud, Ø. (2015). The cytokine-mediated crosstalk between primary human acute myeloid cells and mesenchymal stem cells alters the local cytokine network and the global gene expression profile of the mesenchymal cells. Stem Cell Res., 15(3), 530-541. https://doi.org/10.1016/j.scr.2015.09.008 Reikvam, H., Fredly, H., Kittang, A., y Bruserud, Ø. (2013). The Possible Diagnostic and Prognostic Use of Systemic Chemokine Profiles in Clinical Medicine—The Experience in Acute Myeloid Leukemia from Disease Development and Diagnosis via Conventional Chemotherapy to Allogeneic Stem Cell Transplantation. Toxins, 5(2), 336-362. https://doi.org/10.3390/toxins5020336 Ruiz-Aparicio, P. F., Vanegas, N.-D. P., Uribe, G. I., Ortiz-Montero, P., Cadavid-Cortés, C., Lagos, J., Flechas-Afanador, J., Linares-Ballesteros, A., y Vernot, J.-P. (2020). Dual Targeting of Stromal Cell Support and Leukemic Cell Growth by a Peptidic PKC Inhibitor Shows Effectiveness against B-ALL. Int. J. Mol. Sci., 21(10), 3705. https://doi.org/10.3390/ijms21103705 Rustom, A., Saffrich, R., Markovic, I., Walther, P., y Gerdes, H. H. (2004). Nanotubular Highways for Intercellular Organelle Transport. Science, 303(5660). https://doi.org/10.1126/science.1093133 Schepers, K., Pietras, E. M., Reynaud, D., Flach, J., Binnewies, M., Garg, T., Wagers, A. J., Hsiao, E. C., y Passegué, E. (2013). Myeloproliferative Neoplasia Remodels the Endosteal Bone Marrow Niche into a Self-Reinforcing Leukemic Niche. Cell Stem Cell, 13(3), 285-299. https://doi.org/10.1016/j.stem.2013.06.009 Schinke, C., Giricz, O., Li, W., Shastri, A., Gordon, S., Barreyro, L., Bhagat, T., Bhattacharyya, S., Ramachandra, N., Bartenstein, M., Pellagatti, A., Boultwood, J., Wickrema, A., Yu, Y., Will, B., Wei, S., Steidl, U., y Verma, A. (2015). IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells. Blood, 125(20), 3144-3152. https://doi.org/10.1182/blood-2015-01-621631 Schultz, K. R., Pullen, D. J., Sather, H. N., Shuster, J. J., Devidas, M., Borowitz, M. J., Carroll, A. J., Heerema, N. A., Rubnitz, J. E., Loh, M. L., Raetz, E. A., Winick, N. J., Hunger, S. P., Carroll, W. L., Gaynon, P. S., y Camitta, B. M. (2007). Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG). Blood, 109(3), 926-935. https://doi.org/10.1182/blood-2006-01-024729 Severe, N., Karabacak, N. M., Gustafsson, K., Baryawno, N., Courties, G., Kfoury, Y., Kokkaliaris, K. D., Rhee, C., Lee, D., Scadden, E. W., Garcia-Robledo, J. E., Brouse, T., Nahrendorf, M., Toner, M., y Scadden, D. T. (2019). Stress-Induced Changes in Bone Marrow Stromal Cell Populations Revealed through Single-Cell Protein Expression Mapping. Cell Stem Cell, 25(4), 570-583.e7. https://doi.org/10.1016/j.stem.2019.06.003 Shain, K. H., Yarde, D. N., Meads, M. B., Huang, M., Jove, R., Hazlehurst, L. A., y Dalton, W. S. (2009). β1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: Implications for microenvironment influence on tumor survival and proliferation. Cancer Res., 69(3). https://doi.org/10.1158/0008-5472.CAN-08-2419 Shchemelinin, I., Sefc, L., y Necas, E. (2006). Protein kinases, their function and implication in cancer and other diseases. Folia biologica, 52(3), 81-100. http://www.ncbi.nlm.nih.gov/pubmed/17089919 Shiga, K., Hara, M., Nagasaki, T., Sato, T., Takahashi, H., y Takeyama, H. (2015). Cancer-associated fibroblasts: Their characteristics and their roles in tumor growth. En Cancers (Vol. 7, Número 4). https://doi.org/10.3390/cancers7040902 Shih, V. F.-S., Tsui, R., Caldwell, A., y Hoffmann, A. (2011). A single NFκB system for both canonical and non-canonical signaling. Cell Res., 21(1), 86-102. https://doi.org/10.1038/cr.2010.161 Steinberg, S. F. (2008). Structural Basis of Protein Kinase C Isoform Function. Physiol. Rev., 88(4), 1341-1378. https://doi.org/10.1152/physrev.00034.2007 Strzyz, P. (2019). The unusual SASPects. Nat. Rev. Mol. Cell Biol., 20(4), 195-195. https://doi.org/10.1038/s41580-019-0111-9 Sun, X. y Kaufman, P. D. (2018). Ki-67: more than a proliferation marker. En Chromosoma. https://doi.org/10.1007/s00412-018-0659-8 Takami, M., Katayama, K., Noguchi, K., y Sugimoto, Y. (2018). Protein kinase C alpha-mediated phosphorylation of PIM-1L promotes the survival and proliferation of acute myeloid leukemia cells. Biochemical and Biophysical Research Communications, 503(3). https://doi.org/10.1016/j.bbrc.2018.07.049 Tamaoki, T., Nomoto, H., Takahashi, I., Kato, Y., Morimoto, M., y Tomita, F. (1986). Staurosporine, a potent inhibitor of phospholipidCa++dependent protein kinase. Biochem. Biophys. Res. Commun., 135(2), 397-402. https://doi.org/10.1016/0006-291X(86)90008-2 Tasian, S. K. y Loh, M. L. (2011). Understanding the biology of CRLF2-overexpressing acute lymphoblastic leukemia. Crit Rev Oncog. https://doi.org/10.1615/CritRevOncog.v16.i1-2.30 Teicher, B. A. y Fricker, S. P. (2010). CXCL12 (SDF-1)/CXCR4 pathway in cancer. En Clinical Cancer Research (Vol. 16, Número 11). https://doi.org/10.1158/1078-0432.CCR-09-2329 Tobler, A., Moser, B., Dewald, B., Geiser, T., Studer, H., Baggiolini, M., y Fey, M. (1993). Constitutive expression of interleukin-8 and its receptor in human myeloid and lymphoid leukemia. Blood, 82(8), 2517-2525. https://doi.org/10.1182/blood.V82.8.2517.bloodjournal8282517 Traer, E., MacKenzie, R., Snead, J., Agarwal, A., Eiring, A. M., O’Hare, T., Druker, B. J., y Deininger, M. W. (2012). Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors. Leukemia, 26(5), 1140-1143. https://doi.org/10.1038/leu.2011.325 Turinetto, V., Vitale, E., y Giachino, C. (2016). Senescence in Human Mesenchymal Stem Cells: Functional Changes and Implications in Stem Cell-Based Therapy. Int. J. Mol. Sci., 17(7), 1164. https://doi.org/10.3390/ijms17071164 Van Etten, R. A. (2007). Aberrant cytokine signaling in leukemia. Oncogene, 26(47), 6738-6749. https://doi.org/10.1038/sj.onc.1210758 Vanegas, N.-D. P. y Vernot, J.-P. (2017). Loss of quiescence and self-renewal capacity of hematopoietic stem cell in an in vitro leukemic niche. Exp. Hematol. Oncol., 6(1), 2. https://doi.org/10.1186/s40164-016-0062-1 Vernot, J.-P., Bonilla, X., Rodriguez-Pardo, V., y Vanegas, N.-D. P. (2017). Phenotypic and Functional Alterations of Hematopoietic Stem and Progenitor Cells in an In Vitro Leukemia-Induced Microenvironment. Int. J. Mol. Sci., 18(2), 199. https://doi.org/10.3390/ijms18020199 Vilchis-Ordoñez, A., Contreras-Quiroz, A., Vadillo, E., Dorantes-Acosta, E., Reyes-López, A., Quintela-Nuñez Del Prado, H. M., Venegas-Vázquez, J., Mayani, H., Ortiz-Navarrete, V., López-Martínez, B., y Pelayo, R. (2015). Bone marrow cells in acute lymphoblastic leukemia create a proinflammatory microenvironment influencing normal hematopoietic differentiation fates. Biomed Res. Int. https://doi.org/10.1155/2015/386165 Vitale, I., Manic, G., De Maria, R., Kroemer, G., y Galluzzi, L. (2017). DNA Damage in Stem Cells. Mol Cell, 66(3), 306-319. https://doi.org/10.1016/j.molcel.2017.04.006 Wagner, W., Horn, P., Castoldi, M., Diehlmann, A., Bork, S., Saffrich, R., Benes, V., Blake, J., Pfister, S., Eckstein, V., y Ho, A. D. (2008). Replicative Senescence of Mesenchymal Stem Cells: A Continuous and Organized Process. PLoS ONE, 3(5), e2213. https://doi.org/10.1371/journal.pone.0002213 Walkley, C. R., Olsen, G. H., Dworkin, S., Fabb, S. A., Swann, J., McArthur, G. A., Westmoreland, S. V., Chambon, P., Scadden, D. T., y Purton, L. E. (2007). A Microenvironment-Induced Myeloproliferative Syndrome Caused by Retinoic Acid Receptor γ Deficiency. Cell, 129(6), 1097-1110. https://doi.org/10.1016/j.cell.2007.05.014 Wallace, S. R., Oken, M. M., Lunetta, K. L., Panoskaltsis-Mortari, A., y Masellis, A. M. (2001). Abnormalities of bone marrow mesenchymal cells in multiple myeloma patients. Cancer, 91(7), 1219-1230. https://doi.org/10.1002/1097-0142(20010401)91:7<1219::AID-CNCR1122>3.0.CO;2-1 Weisberg, E., Azab, A. K., Manley, P. W., Kung, A. L., Christie, A. L., Bronson, R., Ghobrial, I. M., y Griffin, J. D. (2012). Inhibition of CXCR4 in CML cells disrupts their interaction with the bone marrow microenvironment and sensitizes them to nilotinib. Leukemia, 26(5), 985-990. https://doi.org/10.1038/leu.2011.360 Windisch, R., Pirschtat, N., Kellner, C., Chen-Wichmann, L., Lausen, J., Humpe, A., Krause, D., y Wichmann, C. (2019). Oncogenic Deregulation of Cell Adhesion Molecules in Leukemia. Cancers, 11(3), 311. https://doi.org/10.3390/cancers11030311 Xu, S., De Veirman, K., De Becker, A., Vanderkerken, K., y Van Riet, I. (2018). Mesenchymal stem cells in multiple myeloma: a therapeutical tool or target? Leukemia, 32(7), 1500-1514. https://doi.org/10.1038/s41375-018-0061-9 Zambetti, N. A., Ping, Z., Chen, S., Kenswil, K. J. G., Mylona, M. A., Sanders, M. A., Hoogenboezem, R. M., Bindels, E. M. J., Adisty, M. N., Van Strien, P. M. H., van der Leije, C. S., Westers, T. M., Cremers, E. M. P., Milanese, C., Mastroberardino, P. G., van Leeuwen, J. P. T. M., van der Eerden, B. C. J., Touw, I. P., Kuijpers, T. W., … Raaijmakers, M. H. G. P. (2016). Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia. Cell Stem Cell, 19(5). https://doi.org/10.1016/j.stem.2016.08.021 Zhang, B., Ho, Y. W., Huang, Q., Maeda, T., Lin, A., Lee, S., Hair, A., Holyoake, T. L., Huettner, C., y Bhatia, R. (2012). Altered Microenvironmental Regulation of Leukemic and Normal Stem Cells in Chronic Myelogenous Leukemia. Cancer Cell, 21(4), 577-592. https://doi.org/10.1016/j.ccr.2012.02.018 Zhang, B., Li, M., McDonald, T., Holyoake, T. L., Moon, R. T., Campana, D., Shultz, L., y Bhatia, R. (2013). Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt–β-catenin signaling. Blood, 121(10), 1824-1838. https://doi.org/10.1182/blood-2012-02-412890 Zhao, Z.-G., Liang, Y., Li, K., Li, W.-M., Li, Q.-B., Chen, Z.-C., y Zou, P. (2007). Phenotypic and Functional Comparison of Mesenchymal Stem Cells Derived from the Bone Marrow of Normal Adults and Patients with Hematologic Malignant Diseases. Stem Cells Dev., 16(4), 637-648. https://doi.org/10.1089/scd.2007.0008 Zheng, Y., Tu, C., Zhang, J., y Wang, J. (2019). Inhibition of multiple myeloma‑derived exosomes uptake suppresses the functional response in bone marrow stromal cell. Int. J. Oncol., 54(3). https://doi.org/10.3892/ijo.2019.4685 Zhou, D., Shao, L., y Spitz, D. R. (2014). Reactive Oxygen Species in Normal and Tumor Stem Cells. En Adv. Cancer Res. (pp. 1-67). https://doi.org/10.1016/B978-0-12-420117-0.00001-3 |
| dc.rights.coar.fl_str_mv |
http://purl.org/coar/access_right/c_abf2 |
| dc.rights.license.spa.fl_str_mv |
Atribución-NoComercial 4.0 Internacional |
| dc.rights.uri.spa.fl_str_mv |
http://creativecommons.org/licenses/by-nc/4.0/ |
| dc.rights.accessrights.spa.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
Atribución-NoComercial 4.0 Internacional http://creativecommons.org/licenses/by-nc/4.0/ http://purl.org/coar/access_right/c_abf2 |
| eu_rights_str_mv |
openAccess |
| dc.format.extent.spa.fl_str_mv |
xix, 225 páginas |
| dc.format.mimetype.spa.fl_str_mv |
application/pdf |
| dc.publisher.spa.fl_str_mv |
Universidad Nacional de Colombia |
| dc.publisher.program.spa.fl_str_mv |
Bogotá - Medicina - Doctorado en Ciencias Biomédicas |
| dc.publisher.faculty.spa.fl_str_mv |
Facultad de Medicina |
| dc.publisher.place.spa.fl_str_mv |
Bogotá - Colombia |
| dc.publisher.branch.spa.fl_str_mv |
Universidad Nacional de Colombia - Sede Bogotá |
| institution |
Universidad Nacional de Colombia |
| bitstream.url.fl_str_mv |
https://repositorio.unal.edu.co/bitstream/unal/80304/1/license.txt https://repositorio.unal.edu.co/bitstream/unal/80304/2/1010195476.2021.pdf https://repositorio.unal.edu.co/bitstream/unal/80304/3/1010195476.2021.pdf.jpg |
| bitstream.checksum.fl_str_mv |
cccfe52f796b7c63423298c2d3365fc6 32987381d74b1f9fc82beb3120db91ba 840841a8dda2a2b1fa8cc3a5b45f1fe8 |
| bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 |
| repository.name.fl_str_mv |
Repositorio Institucional Universidad Nacional de Colombia |
| repository.mail.fl_str_mv |
repositorio_nal@unal.edu.co |
| _version_ |
1814089925699567616 |
| spelling |
Atribución-NoComercial 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Vernot, Jean-Paulc50cef4e56149a8166ab723898167f35Vanegas Avendaño, Natalia-Del Pilar9ba8b2373d1d2ad81e9492e486f9b1bc600Fisiología Celular y Molecular2021-09-24T22:20:14Z2021-09-24T22:20:14Z2021https://repositorio.unal.edu.co/handle/unal/80304Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/gráficas, ilustraciones, tablasEl microambiente de la médula ósea (MO) impacta de manera importante la progresión de la leucemia, favoreciendo la supervivencia y la resistencia a la muerte celular. Las mesenchymal stem cells (MSC) constituyen una población celular importante del nicho hematopoyético de la MO, sin embargo, su funcionalidad se ve afectada de manera importante por el estrés celular inducido por el crecimiento de las células leucémicas, con consecuencias desfavorables para las células stem hematopoyéticas en favor de las células leucémicas. Se ha demostrado un papel de la proteína quinasa C (PKC) estromal en el soporte, supervivencia y proliferación de varios tipos de leucemia. Las alteraciones de las MSC en la leucemia linfoblástica aguda de células B (LLA-B) solo han sido estudiadas parcialmente. En este trabajo, se mostró que la inhibición específica de la PKC con un péptido quimérico HKPS induce una reducción de la viabilidad, entre un 45 y 60%, de las células leucémicas de pacientes con LLA-B. También, se estudiaron las modificaciones de las MSC en un nicho leucémico in vitro, y en MSC aisladas de pacientes con LLA-B. Las MSC mostraron características de un proceso senescente con pérdida de su morfología fibroblastoide con células aplanadas con aumento de su área citoplasmática, un aumento en la actividad β-galactosidasa asociada a senescencia (SA-βGAL) y en la transcripción de los genes p53 y p21, también la detención del ciclo celular, una reducida clonogenicidad y la generación transitoria de especies reactivas de oxígeno (ROS) citosólico y mitocondrial, siendo las células leucémicas las reguladoras positivas para la inducción de este proceso. En particular, una disfunción moderada en las propiedades stemness, con una proliferación reducida, una pérdida de la capacidad de diferenciación osteoblástica y un aumento de la diferenciación adipogénica y, con un aumento en su capacidad de autorrenovación. Características reportadas en MSC senescentes que, se asocian con la inflamación y, la activación de la vía NF-B encontrada en el modelo in vitro. En este modelo se encontró que, el retiro de las células leucémicas del co-cultivo y el cultivo extendido de las MSC senescentes con un estímulo proliferante (SFB) induce el re-ingreso al ciclo celular y una disminución de la SA-βGAL, sugiriendo una reversión del fenotipo senescente con la reaparición parcial de las propiedades de stem. Además, solo una pequeña población de MSC acumuló daño al DNA por la fosforilación de H2AX que además se redujo a niveles basales después del cultivo. También se encontró un perfil claro de citoquinas y quimioquinas pro-inflamatorias (CCL2, IL-8, IL-6), característico de un fenotipo secretor asociado a la senescencia (SASP) en el NL, que fundamenta las acciones de las MSC en el microambiente leucémico a través de mecanismos paracrinos y el cual fue mediado por la actividad de la PKC. En conclusión, la afectación que sufren las MSC requiere de la presencia permanente de células leucémicas, y cuando se retira el estrés leucémico, las MSC retoman prácticamente a su funcionamiento normal. Estos hallazgos son de gran relevancia en la progresión de la enfermedad y en el tratamiento.(Texto tomado de la fuente)The bone marrow (BM) microenvironment influences dramatically leukemia progression by favoring survival and resistance to cell death. Mesenchymal stem cells (MSC) constitute an important cell population of the BM hematopoietic niche; however, most of their functions are significantly affected by cellular stress imposed by leukemic cell growth, with unfavorable consequences for hematopoietic stem cells in favor of leukemic cells. A role of stromal protein kinase C (PKC) in the support, survival and proliferation of various types of leukemia has been demonstrated. MSC alterations in B-cell acute lymphoblastic leukemia (B-ALL) have only been partially studied. In this work, we showed that specific inhibition of PKC with a chimeric HKPS peptide induces a 45-60% reduction in viability of leukemic cells from B-ALL patients. Also, MSC modifications were studied in a leukemic niche (LN) in vitro, and in MSC isolated from B-ALL patients. MSC showed features of a senescent process with loss of their fibroblastoid morphology with flattened cells with increased cytoplasmic area and increase in senescence-associated β-galactosidase (SA-βGAL) activity and in the expression of p53 and p21 genes, cell cycle arrest, reduced clonogenicity and transient generation of intracellular and mitochondrial reactive oxygen species (ROS), with leukemic cells being the inducers and regulators of this process. A moderate dysfunction in stemness properties, with reduced proliferation, loss of osteoblastic differentiation capacity, increased adipogenic differentiation and an increase in their self-renewal capacity were also found. In the in vitro model, it was found that, removal of leukemic cells followed by further culture with a proliferating stimulus induced re-entry into the cell cycle and a decrease in SA-βGAL, suggesting a reversal of the senescent phenotype with partial reappearance of stem-like cell properties. Accordingly, only a small population of MSC accumulated DNA damage by H2AX phosphorylation which was reduced to basal levels after culture. A clear pro-inflammatory cytokine and chemokine profile characteristic of a senescence-associated secretory phenotype (SASP) was also found in the LN (CCL2, IL-8, IL-6), validating MSC role in the leukemic microenvironment through paracrine mechanisms and which was mediated by PKC activity. In conclusion, MSC impairment requires the presence of leukemic cells, and when leukemic stress is removed, MSC almost recovered normal function. These findings are of great relevance in disease progression and treatment.DoctoradoDoctor en Ciencias Biomédicasxix, 225 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Medicina - Doctorado en Ciencias BiomédicasFacultad de MedicinaBogotá - ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud570 - BiologíaLeucemia linfoblástica aguda de células B (LLA-B)MSC del co-cultivo (MSC-CO)Proteína quinasa C (PKC)Nicho leucémico (NL)Microambiente de la médula ósea (MO)Senescencia reversiblePro-inflamatorioMesenchymal stem cells (MSC)B-cell acute lymphoblastic leukemia (B-ALL)Leukemic niche (LN)MSC from co-culture (MSC-CO)Protein kinase C (PKC)Bone marrow (BM) microenvironmentReversible senescencePro-inflammatoryPapel de la proteína quinasa C (PKC) en el crecimiento de células de leucemia linfoide aguda tipo B, en el soporte que les proporcionan las células stem mesenquimales y en su funcionalidad en un modelo in vitro de nicho leucémicoRole of protein kinase C (PKC) in the growth of B-cell acute lymphoblastic leukemia cells, in the support provided by mesenchymal stem cells and in their functionality in an in vitro model of leukemic niche.Trabajo de grado - Doctoradoinfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionImageTexthttp://purl.org/redcol/resource_type/TMAbdul-Aziz, A. M., Shafat, M. S., Mehta, T. K., Di Palma, F., Lawes, M. J., Rushworth, S. A., y Bowles, K. M. (2017). MIF-induced stromal PKCβ/IL8 is essential in human acute myeloid leukemia. Cancer Research, 77(2). https://doi.org/10.1158/0008-5472.CAN-16-1095Abdul-Aziz, A. M., Sun, Y., Hellmich, C., Marlein, C. R., Mistry, J., Forde, E., Piddock, R. E., Shafat, M. S., Morfakis, A., Mehta, T., Di Palma, F., Macaulay, I., Ingham, C. J., Haestier, A., Collins, A., Campisi, J., Bowles, K. M., y Rushworth, S. A. (2019). Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment. Blood, 133(5), 446-456. https://doi.org/10.1182/blood-2018-04-845420Abrams, S. T., Lakum, T., Lin, K., Jones, G. M., Treweeke, A. T., Farahani, M., Hughes, M., Zuzel, M., y Slupsky, J. R. (2007). B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CβII. Blood, 109(3), 1193-1201. https://doi.org/10.1182/blood-2006-03-012021Acuña, L., Sánchez, P., Uribe, D., Pulido, D., y Valencia, O. (2015). Situación del cáncer en Colombia 2015. https://doi.org/Book_Doi 10.1201/9781420072884André, T., Meuleman, N., Stamatopoulos, B., De Bruyn, C., Pieters, K., Bron, D., y Lagneaux, L. (2013). Evidences of Early Senescence in Multiple Myeloma Bone Marrow Mesenchymal Stromal Cells. PLoS ONE, 8(3), e59756. https://doi.org/10.1371/journal.pone.0059756Antonsson, A. y Persson, J. L. (2009). Induction of apoptosis by staurosporine involves the inhibition of expression of the major cell cycle proteins at the G(2)/m checkpoint accompanied by alterations in Erk and Akt kinase activities. Anticancer Res., 29(8), 2893-2898. http://www.ncbi.nlm.nih.gov/pubmed/19661292Arnulf, B., Lecourt, S., Soulier, J., Ternaux, B., Lacassagne, M.-N., Crinquette, A., Dessoly, J., Sciaini, A.-K., Benbunan, M., Chomienne, C., Fermand, J.-P., Marolleau, J.-P., y Larghero, J. (2007). Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma. Leukemia, 21(1), 158-163. https://doi.org/10.1038/sj.leu.2404466Arranz, L., Sánchez-Aguilera, A., Martín-Pérez, D., Isern, J., Langa, X., Tzankov, A., Lundberg, P., Muntión, S., Tzeng, Y. S., Lai, D. M., Schwaller, J., Skoda, R. C., y Méndez-Ferrer, S. (2014). Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature, 512(1). https://doi.org/10.1038/nature13383Baker, R. G., Hayden, M. S., y Ghosh, S. (2011). NF-κB, inflammation, and metabolic disease. En Cell Metabolism. https://doi.org/10.1016/j.cmet.2010.12.008Barragán, M., Bellosillo, B., Campàs, C., Colomer, D., Pons, G., y Gil, J. (2002). Involvement of protein kinase C and phosphatidylinositol 3–kinase pathways in the survival of B-cell chronic lymphocytic leukemia cells. Blood, 99(8), 2969-2976. https://doi.org/10.1182/blood.V99.8.2969Baryawno, N., Przybylski, D., Kowalczyk, M. S., Kfoury, Y., Severe, N., Gustafsson, K., Kokkaliaris, K. D., Mercier, F., Tabaka, M., Hofree, M., Dionne, D., Papazian, A., Lee, D., Ashenberg, O., Subramanian, A., Vaishnav, E. D., Rozenblatt-Rosen, O., Regev, A., y Scadden, D. T. (2019). A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia. Cell, 177(7), 1915-1932.e16. https://doi.org/10.1016/j.cell.2019.04.040Beauséjour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., y Campisi, J. (2003). Reversal of human cellular senescence: Roles of the p53 and p16 pathways. EMBO J, 22(16), 4212-4222. https://doi.org/10.1093/emboj/cdg417Belmokhtar, C. A., Hillion, J., y Ségal-Bendirdjian, E. (2001). Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms. Oncogene, 20(26), 3354-3362. https://doi.org/10.1038/sj.onc.1204436Ben-Neriah, Y. y Karin, M. (2011). Inflammation meets cancer, with NF-κB as the matchmaker. Nat. Immunol., 12(8), 715-723. https://doi.org/10.1038/ni.2060Berenstein, R., Blau, O., Nogai, A., Waechter, M., Slonova, E., Schmidt-Hieber, M., Kunitz, A., Pezzutto, A., Doerken, B., y Blau, I. W. (2015). Multiple myeloma cells alter the senescence phenotype of bone marrow mesenchymal stromal cells under participation of the DLK1-DIO3 genomic region. BMC Cancer, 15(1), 68. https://doi.org/10.1186/s12885-015-1078-3Bernardo, M. E., Zaffaroni, N., Novara, F., Cometa, A. M., Avanzini, M. A., Moretta, A., Montagna, D., Maccario, R., Villa, R., Daidone, M. G., Zuffardi, O., y Locatelli, F. (2007). Human bone marrow-derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-06-4690Bhat, A. H., Dar, K. B., Anees, S., Zargar, M. A., Masood, A., Sofi, M. A., y Ganie, S. A. (2015). Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. En Biomedicine and Pharmacotherapy (Vol. 74). https://doi.org/10.1016/j.biopha.2015.07.025Bhatia, B., Multani, A. S., Patrawala, L., Chen, X., Calhoun-Davis, T., Zhou, J., Schroeder, L., Schneider-Broussard, R., Shen, J., Pathak, S., Chang, S., y Tang, D. G. (2007). Evidence that senescent human prostate epithelial cells enhance tumorigenicity: Cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT. Int. J. Cancer, 122(7), 1483-1495. https://doi.org/10.1002/ijc.23222Bhojwani, D. y Pui, C. H. (2013). Relapsed childhood acute lymphoblastic leukaemia. En Lancet Oncol. https://doi.org/10.1016/S1470-2045(12)70580-6Blaser, H., Dostert, C., Mak, T. W., y Brenner, D. (2016). TNF and ROS Crosstalk in Inflammation. En Trends in Cell Biology (Vol. 26, Número 4). https://doi.org/10.1016/j.tcb.2015.12.002Bonilla, X., Vanegas, N.-D. P., y Vernot, J. P. (2019). Acute Leukemia Induces Senescence and Impaired Osteogenic Differentiation in Mesenchymal Stem Cells Endowing Leukemic Cells with Functional Advantages. Stem Cells Int, 2019, 1-16. https://doi.org/10.1155/2019/3864948Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., y Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J. Clin., 68(6), 394-424. https://doi.org/10.3322/caac.21492Brenner, A. K., Reikvam, H., y Bruserud, Ø. (2016). A Subset of Patients with Acute Myeloid Leukemia Has Leukemia Cells Characterized by Chemokine Responsiveness and Altered Expression of Transcriptional as well as Angiogenic Regulators. Front Immunol, 7(MAY). https://doi.org/10.3389/fimmu.2016.00205Brücher, B. L. D. M. y Jamall, I. S. (2014). Cell-cell communication in the tumor microenvironment, carcinogenesis, and anticancer treatment. En Cellular Physiology and Biochemistry (Vol. 34, Número 2). https://doi.org/10.1159/000362978Burger, J. A., Tsukada, N., Burger, M., Zvaifler, N. J., Dell’Aquila, M., y Kipps, T. J. (2000). Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell–derived factor-1. Blood, 96(8), 2655-2663. https://doi.org/10.1182/blood.V96.8.2655Canli, Ö., Nicolas, A. M., Gupta, J., Finkelmeier, F., Goncharova, O., Pesic, M., Neumann, T., Horst, D., Löwer, M., Sahin, U., y Greten, F. R. (2017). Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis. Cancer Cell, 32(6). https://doi.org/10.1016/j.ccell.2017.11.004Chauhan, D., Uchiyama, H., Akbarali, Y., Urashima, M., Yamamoto, K., Libermann, T., y Anderson, K. (1996). Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood, 87(3), 1104-1112. https://doi.org/10.1182/blood.V87.3.1104.bloodjournal8731104Chen, X., Li, N., Weng, J., y Du, X. (2021). Senescent Mesenchymal Stem Cells in Myelodysplastic Syndrome: Functional Alterations, Molecular Mechanisms, and Therapeutic Strategies. En Frontiers in Cell and Developmental Biology (Vol. 8). https://doi.org/10.3389/fcell.2020.617466Cheung, L. C., Tickner, J., Hughes, A. M., Skut, P., Howlett, M., Foley, B., Oommen, J., Wells, J. E., He, B., Singh, S., Chua, G.-A., Ford, J., Mullighan, C. G., Kotecha, R. S., y Kees, U. R. (2018). New therapeutic opportunities from dissecting the pre-B leukemia bone marrow microenvironment. Leukemia, 32(11), 2326-2338. https://doi.org/10.1038/s41375-018-0144-7Childs, B. G., Baker, D. J., Kirkland, J. L., Campisi, J., y Deursen, J. M. (2014). Senescence and apoptosis: dueling or complementary cell fates? EMBO reports. https://doi.org/10.15252/embr.201439245Cidado, J., Wong, H. Y., Marc Rosen, D., Cimino-Mathews, A., Garay, J. P., Fessler, A. G., Rasheed, Z. A., Hicks, J., Cochran, R. L., Croessmann, S., Zabransky, D. J., Mohseni, M., Beaver, J. A., Chu, D., Cravero, K., Christenson, E. S., Medford, A., Mattox, A., De Marzo, A. M., … Park, B. H. (2016). Ki-67 is required for maintenance of cancer stem cells but not cell proliferation. Oncotarget. https://doi.org/10.18632/oncotarget.7057Cimmino, A., Calin, G. A., Fabbri, M., Iorio, M. V., Ferracin, M., Shimizu, M., Wojcik, S. E., Aqeilan, R. I., Zupo, S., Dono, M., Rassenti, L., Alder, H., Volinia, S., Liu, C. -g., Kipps, T. J., Negrini, M., y Croce, C. M. (2005). miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl. Acad. Sci. U.S.A., 102(39), 13944-13949. https://doi.org/10.1073/pnas.0506654102Conforti, A., Biagini, S., Del Bufalo, F., Sirleto, P., Angioni, A., Starc, N., Li Pira, G., Moretta, F., Proia, A., Contoli, B., Genovese, S., Ciardi, C., Avanzini, M. A., Rosti, V., Lo-Coco, F., Locatelli, F., y Bernardo, M. E. (2013). Biological, Functional and Genetic Characterization of Bone Marrow-Derived Mesenchymal Stromal Cells from Pediatric Patients Affected by Acute Lymphoblastic Leukemia. PLoS ONE, 8(11), e76989. https://doi.org/10.1371/journal.pone.0076989Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P. Y., y Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. https://doi.org/10.1371/journal.pbio.0060301Corradi, G., Baldazzi, C., Očadlíková, D., Marconi, G., Parisi, S., Testoni, N., Finelli, C., Cavo, M., Curti, A., y Ciciarello, M. (2018). Mesenchymal stromal cells from myelodysplastic and acute myeloid leukemia patients display in vitro reduced proliferative potential and similar capacity to support leukemia cell survival. Stem Cell Res. Ther., 9(1), 271. https://doi.org/10.1186/s13287-018-1013-zCorre, J., Mahtouk, K., Attal, M., Gadelorge, M., Huynh, A., Fleury-Cappellesso, S., Danho, C., Laharrague, P., Klein, B., Rème, T., y Bourin, P. (2007). Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia, 21(5), 1079-1088. https://doi.org/10.1038/sj.leu.2404621Cosentino-Gomes, D., Rocco-Machado, N., y Meyer-Fernandes, J. R. (2012). Cell Signaling through Protein Kinase C Oxidation and Activation. Int. J. Mol. Sci., 13(9), 10697-10721. https://doi.org/10.3390/ijms130910697DANE. (2018). Defunciones Estadísticas Vitales. http://systema74.dane.gov.co/bincol/RpWebEngine.exe/Portal?BASE=DEFOC08&lang=espDarwish, N. H. E., Sudha, T., Godugu, K., Bharali, D. J., Elbaz, O., El-ghaffar, H. A. A., Azmy, E., Anber, N., y Mousa, S. A. (2019). Novel Targeted Nano-Parthenolide Molecule against NF-kB in Acute Myeloid Leukemia. Molecules, 24(11), 2103. https://doi.org/10.3390/molecules24112103Davalli, P., Mitic, T., Caporali, A., Lauriola, A., y D’Arca, D. (2016). ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases. Oxid. Med. Cell. Longev., 2016, 1-18. https://doi.org/10.1155/2016/3565127de Vasconcellos, J. F., Laranjeira, A. B. A., Zanchin, N. I. T., Otubo, R., Vaz, T. H., Cardoso, A. A., Brandalise, S. R., y Yunes, J. A. (2011). Increased CCL2 and IL-8 in the bone marrow microenvironment in acute lymphoblastic leukemia. Pediatr. Blood Cancer, 56(4), 568-577. https://doi.org/10.1002/pbc.22941Den Boer, M. L., van Slegtenhorst, M., De Menezes, R. X., Cheok, M. H., Buijs-Gladdines, J. G., Peters, S. T., Van Zutven, L. J., Beverloo, H. B., Van der Spek, P. J., Escherich, G., Horstmann, M. A., Janka-Schaub, G. E., Kamps, W. A., Evans, W. E., y Pieters, R. (2009). A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. https://doi.org/10.1016/S1470-2045(08)70339-5Denizot, Y., Fixe, P., Liozon, E., y Praloran, V. (1996). Serum interleukin-8 (IL-8) and IL-6 concentrations in patients with hematologic malignancies [letter]. Blood, 87(9), 4016-4017. https://doi.org/10.1182/blood.V87.9.4016.bloodjournal8794016Dierks, C., Grbic, J., Zirlik, K., Beigi, R., Englund, N. P., Guo, G.-R., Veelken, H., Engelhardt, M., Mertelsmann, R., Kelleher, J. F., Schultz, P., y Warmuth, M. (2007). Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med, 13(8), 944-951. https://doi.org/10.1038/nm1614Ding, W., Nowakowski, G. S., Knox, T. R., Boysen, J. C., Maas, M. L., Schwager, S. M., Wu, W., Wellik, L. E., Dietz, A. B., Ghosh, A. K., Secreto, C. R., Medina, K. L., Shanafelt, T. D., Zent, C. S., Call, T. G., y Kay, N. E. (2009). Bi-directional activation between mesenchymal stem cells and CLL B-cells: implication for CLL disease progression. Br. J. Haematol., 147(4), 471-483. https://doi.org/10.1111/j.1365-2141.2009.07868.xDominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F. ., Krause, D. S., Deans, R. J., Keating, A., Prockop, D. J., y Horwitz, E. M. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8(4), 315-317. https://doi.org/10.1080/14653240600855905Duarte, D., Hawkins, E. D., y Lo Celso, C. (2018). The interplay of leukemia cells and the bone marrow microenvironment. En Blood (Vol. 131, Número 14). https://doi.org/10.1182/blood-2017-12-784132Ebinger, S., Özdemir, E. Z., Ziegenhain, C., Tiedt, S., Castro Alves, C., Grunert, M., Dworzak, M., Lutz, C., Turati, V. A., Enver, T., Horny, H.-P., Sotlar, K., Parekh, S., Spiekermann, K., Hiddemann, W., Schepers, A., Polzer, B., Kirsch, S., Hoffmann, M., … Jeremias, I. (2016). Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia. Cancer Cell, 30(6), 849-862. https://doi.org/10.1016/j.ccell.2016.11.002Egle, A., Holler, C., Pinon, J. D., Denk, U., Heyder, C., y Greil, R. (2008). PKCβ Is Essential for the Development of CLL in the TCL1 Transgenic Mouse Model: Validation of PKCβ as a Therapeutic Target in CLL. Blood, 112(11), 4164-4164. https://doi.org/10.1182/blood.V112.11.4164.4164El-Gamal, D., Williams, K., LaFollette, T. D., Cannon, M., Blachly, J. S., Zhong, Y., Woyach, J. A., Williams, E., Awan, F. T., Jones, J., Andritsos, L., Maddocks, K., Wu, C.-H., Chen, C.-S., Lehman, A., Zhang, X., Lapalombella, R., y Byrd, J. C. (2014). PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL. Blood, 124(9), 1481-1491. https://doi.org/10.1182/blood-2014-05-574830Garderet, L., Mazurier, C., Chapel, A., Ernou, I., Boutin, L., Holy, X., Gorin, N. C., Lopez, M., Doucet, C., y Lataillade, J.-J. (2007). Mesenchymal stem cell abnormalities in patients with multiple myeloma. Leukemia & Lymphoma, 48(10), 2032-2041. https://doi.org/10.1080/10428190701593644Gill, J. G., Piskounova, E., y Morrison, S. J. (2016). Cancer, oxidative stress, and metastasis. Cold Spring Harbor Symposia on Quantitative Biology, 81(1). https://doi.org/10.1101/sqb.2016.81.030791Giordano, P., Molinari, A. C., Del Vecchio, G. C., Saracco, P., Russo, G., Altomare, M., Perutelli, P., Crescenzio, N., Santoro, N., Marchetti, M., De Mattia, D., y Falanga, A. (2010). Prospective study of hemostatic alterations in children with acute lymphoblastic leukemia. Am. J. Hematol., 85(5), NA-NA. https://doi.org/10.1002/ajh.21665Gnani, D., Crippa, S., della Volpe, L., Rossella, V., Conti, A., Lettera, E., Rivis, S., Ometti, M., Fraschini, G., Bernardo, M. E., y Di Micco, R. (2019). An early‐senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro‐inflammatory program. Aging Cell, 18(3), e12933. https://doi.org/10.1111/acel.12933Gopalakrishna, R. y Jaken, S. (2000). Protein kinase C signaling and oxidative stress. Free Radic. Biol. Med., 28(9), 1349-1361. https://doi.org/10.1016/S0891-5849(00)00221-5Grivennikov, S. I., Greten, F. R., y Karin, M. (2010). Immunity, Inflammation, and Cancer. En Cell (Vol. 140, Número 6). https://doi.org/10.1016/j.cell.2010.01.025Guo, J., Zhao, Y., Fei, C., Zhao, S., Zheng, Q., Su, J., Wu, D., Li, X., y Chang, C. (2018). Dicer1 downregulation by multiple myeloma cells promotes the senescence and tumor-supporting capacity and decreases the differentiation potential of mesenchymal stem cells. Cell Death Dis, 9(5), 512. https://doi.org/10.1038/s41419-018-0545-6Gupta, V. A., Matulis, S. M., Conage-Pough, J. E., Nooka, A. K., Kaufman, J. L., Lonial, S., y Boise, L. H. (2017). Bone marrow microenvironment–derived signals induce Mcl-1 dependence in multiple myeloma. Blood, 129(14), 1969-1979. https://doi.org/10.1182/blood-2016-10-745059Halton, J. M., Atkinson, S. A., Fraher, L., Webber, C. E., Cockshott, W. P., Tam, C., y Barr, R. D. (1995). Mineral homeostasis and bone mass at diagnosis in children with acute lymphoblastic leukemia. J Pediatr, 126(4), 557-564. https://doi.org/10.1016/S0022-3476(95)70349-7Hamidi, H. y Ivaska, J. (2018). Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer., 18(9), 533-548. https://doi.org/10.1038/s41568-018-0038-zHartl, D., Latzin, P., Hordijk, P., Marcos, V., Rudolph, C., Woischnik, M., Krauss-Etschmann, S., Koller, B., Reinhardt, D., Roscher, A. A., Roos, D., y Griese, M. (2007). Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat. Med., 13(12), 1423-1430. https://doi.org/10.1038/nm1690Hayden, M. S. y Ghosh, S. (2008). Shared Principles in NF-κB Signaling. Cell, 132(3), 344-362. https://doi.org/10.1016/j.cell.2008.01.020Hellmich, C., Moore, J. A., Bowles, K. M., y Rushworth, S. A. (2020). Bone Marrow Senescence and the Microenvironment of Hematological Malignancies. En Frontiers in Oncology (Vol. 10). https://doi.org/10.3389/fonc.2020.00230Ho, A. D., Wagner, W., y Franke, W. (2008). Heterogeneity of mesenchymal stromal cell preparations. Cytotherapy, 10(4), 320-330. https://doi.org/10.1080/14653240802217011Houghten, R. A. (1985). General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids. Proc. Natl. Acad. Sci. U.S.A, 82(15), 5131-5135. https://doi.org/10.1073/pnas.82.15.5131Hu, D., Yuan, S., Zhong, J., Liu, Z., Wang, Y., Liu, L., Li, J., Wen, F., Liu, J., y Zhang, J. (2021). Cellular senescence and hematological malignancies: From pathogenesis to therapeutics. En Pharmacology andHunger, S. P. y Mullighan, C. G. (2015). Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine. Blood, 125(26), 3977-3987. https://doi.org/10.1182/blood-2015-02-580043Iannetti, A., Ledoux, A. C., Tudhope, S. J., Sellier, H., Zhao, B., Mowla, S., Moore, A., Hummerich, H., Gewurz, B. E., Cockell, S. J., Jat, P. S., Willmore, E., y Perkins, N. D. (2014). Regulation of p53 and Rb Links the Alternative NF-κB Pathway to EZH2 Expression and Cell Senescence. PLoS Genetics, 10(9). https://doi.org/10.1371/journal.pgen.1004642Imbert, V. y Peyron, J.-F. (2017). NF-κB in Hematological Malignancies. Biomedicines, 5(4), 27. https://doi.org/10.3390/biomedicines5020027Ioanou, K., Cheng, K. F., Crichlow, G. V., Birmpilis, A. I., Lolis, E. J., Tsitsilonis, O. E., y Al-Abed, Y. (2014). ISO-66, a novel inhibitor of macrophage migration inhibitory factor, shows efficacy in melanoma and colon cancer models. International Journal of Oncology, 45(4). https://doi.org/10.3892/ijo.2014.2551Iwamoto, S., Mihara, K., Downing, J. R., Pui, C.-H., y Campana, D. (2007). Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. J Clin Invest, 117(4), 1049-1057. https://doi.org/10.1172/JCI30235Izadpanah, R., Kaushal, D., Kriedt, C., Tsien, F., Patel, B., Dufour, J., y Bunnell, B. A. (2008). Long-term In vitro Expansion Alters the Biology of Adult Mesenchymal Stem Cells. Cancer Res., 68(11), 4229-4238. https://doi.org/10.1158/0008-5472.CAN-07-5272Jacamo, R., Chen, Y., Wang, Z., Ma, W., Zhang, M., Spaeth, E. L., Wang, Y., Battula, V. L., Mak, P. Y., Schallmoser, K., Ruvolo, P., Schober, W. D., Shpall, E. J., Nguyen, M. H., Strunk, D., Bueso-Ramos, C. E., Konoplev, S., Davis, R. E., Konopleva, M., y Andreeff, M. (2014). Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance. Blood, 123(17), 2691-2702. https://doi.org/10.1182/blood-2013-06-511527Jiffar, T., Kurinna, S., Suck, G., Carlson-Bremer, D., Ricciardi, M. R., Konopleva, M., Andreeff, M., y Ruvolo, P. P. (2004). PKC α mediates chemoresistance in acute lymphoblastic leukemia through effects on Bcl2 phosphorylation. Leukemia. https://doi.org/10.1038/sj.leu.2403275Jin, H. J., Lee, H. J., Heo, J., Lim, J., Kim, M., Kim, M. K., Nam, H. Y., Hong, G. H., Cho, Y. S., Choi, S. J., Kim, I. G., Shin, D. M., y Kim, S. W. (2016). Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells. Antioxidants and Redox Signaling. https://doi.org/10.1089/ars.2015.6359Jin, X.-T., Chen, M.-L., Li, R.-J., An, Q., Song, L., Zhao, Y., Xiao, H., Cheng, L., y Li, Z.-Y. (2016). Progression and inflammation of human myeloid leukemia induced by ambient PM2.5 exposure. Arch. Toxicol, 90(8), 1929-1938. https://doi.org/10.1007/s00204-015-1610-xJohmura, Y. y Nakanishi, M. (2016). Multiple facets of p53 in senescence induction and maintenance. Cancer Sci., 107(11), 1550-1555. https://doi.org/10.1111/cas.13060Johnson, S. M., Dempsey, C., Chadwick, A., Harrison, S., Liu, J., Di, Y., McGinn, O. J., Fiorillo, M., Sotgia, F., Lisanti, M. P., Parihar, M., Krishnan, S., y Saha, V. (2016). Metabolic reprogramming of bone marrow stromal cells by leukemic extracellular vesicles in acute lymphoblastic leukemia. Blood, 128(3), 453-456. https://doi.org/10.1182/blood-2015-12-688051Joyce, D., Albanese, C., Steer, J., Fu, M., Bouzahzah, B., y Pestell, R. G. (2001). NF-κB and cell-cycle regulation: The cyclin connection. En Cytokine Growth Factor Rev. https://doi.org/10.1016/S1359-6101(00)00018-6Juneja, H. S., Schmalsteig, F. C., Lee, S., y Chen, J. (1993). Vascular cell adhesion molecule-1 and VLA-4 are obligatory adhesion proteins in the heterotypic adherence between human leukemia/lymphoma cells and marrow stromal cells. Experimental Hematology, 21(3).Karin, M. (2006). Nuclear factor-κB in cancer development and progression. Nature, 441(7092), 431-436. https://doi.org/10.1038/nature04870Keenan, C., Thompson, S., Knox, K., y Pears, C. (1999). Protein Kinase C-α Is Essential for Ramos-BL B Cell Survival. Cell. Immunol., 196(2), 104-109. https://doi.org/10.1006/cimm.1999.1549Kfoury, Y. y Scadden, D. T. (2015). Mesenchymal Cell Contributions to the Stem Cell Niche. Cell Stem Cell, 16(3), 239-253. https://doi.org/10.1016/j.stem.2015.02.019Kim, J.-A., Shim, J.-S., Lee, G.-Y., Yim, H. W., Kim, T.-M., Kim, M., Leem, S.-H., Lee, J.-W., Min, C.-K., y Oh, I.-H. (2015). Microenvironmental Remodeling as a Parameter and Prognostic Factor of Heterogeneous Leukemogenesis in Acute Myelogenous Leukemia. Cancer Res, 75(11), 2222-2231. https://doi.org/10.1158/0008-5472.CAN-14-3379Kim, J.-H., Lee, H.-S., Choi, H.-K., Kim, J.-A., Chu, I.-S., Leem, S.-H., y Oh, I.-H. (2016). Heterogeneous Niche Activity of Ex-Vivo Expanded MSCs as Factor for Variable Outcomes in Hematopoietic Recovery. PLOS ONE, 11(12), e0168036. https://doi.org/10.1371/journal.pone.0168036Kleppe, M., Koche, R., Zou, L., van Galen, P., Hill, C. E., Dong, L., De Groote, S., Papalexi, E., Hanasoge Somasundara, A. V., Cordner, K., Keller, M., Farnoud, N., Medina, J., McGovern, E., Reyes, J., Roberts, J., Witkin, M., Rapaport, F., Teruya-Feldstein, J., … Levine, R. L. (2018). Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell, 33(1), 29-43.e7. https://doi.org/10.1016/j.ccell.2017.11.009Klopp, A. H., Gupta, A., Spaeth, E., Andreeff, M., y Marini, F. (2011). Concise Review: Dissecting a Discrepancy in the Literature: Do Mesenchymal Stem Cells Support or Suppress Tumor Growth? STEM CELLS, 29(1), 11-19. https://doi.org/10.1002/stem.559Konopleva, M., Konoplev, S., Hu, W., Zaritskey, A., Afanasiev, B., y Andreeff, M. (2002). Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia, 16(9), 1713-1724. https://doi.org/10.1038/sj.leu.2402608Krevvata, M., Silva, B. C., Manavalan, J. S., Galan-Diez, M., Kode, A., Matthews, B. G., Park, D., Zhang, C. A., Galili, N., Nickolas, T. L., Dempster, D. W., Dougall, W., Teruya-Feldstein, J., Economides, A. N., Kalajzic, I., Raza, A., Berman, E., Mukherjee, S., Bhagat, G., y Kousteni, S. (2014). Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood, 124(18). https://doi.org/10.1182/blood-2013-07-517219Krtolica, A., Parrinello, S., Lockett, S., Desprez, P.-Y., y Campisi, J. (2001). Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging. Proc Natl Acad Sci U S A, 98(21), 12072-12077. https://doi.org/10.1073/pnas.211053698Kumar, A., Anand, T., Bhattacharyya, J., Sharma, A., y Jaganathan, B. G. (2018). K562 chronic myeloid leukemia cells modify osteogenic differentiation and gene expression of bone marrow stromal cells. J Cell Commun Signal, 12(2), 441-450. https://doi.org/10.1007/s12079-017-0412-8Kurtova, A. V., Balakrishnan, K., Chen, R., Ding, W., Schnabl, S., Quiroga, M. P., Sivina, M., Wierda, W. G., Estrov, Z., Keating, M. J., Shehata, M., Jäger, U., Gandhi, V., Kay, N. E., Plunkett, W., y Burger, J. A. (2009). Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood, 114(20), 4441-4450. https://doi.org/10.1182/blood-2009-07-233718Lagneaux, L., Delforge, A., Bron, D., De Bruyn, C., y Stryckmans, P. (1998). Chronic Lymphocytic Leukemic B Cells But Not Normal B Cells Are Rescued From Apoptosis by Contact With Normal Bone Marrow Stromal Cells. Blood, 91(7), 2387-2396. https://doi.org/10.1182/blood.V91.7.2387.2387_2387_2396Lašťovička, J., Rataj, M., y Bartůňková, J. (2016). Assessment of lymphocyte proliferation for diagnostic purpose: Comparison of CFSE staining, Ki-67 expression and 3H-thymidine incorporation. Human Immunology. https://doi.org/10.1016/j.humimm.2016.08.012Lawrence, T. (2009). The Nuclear Factor NF- B Pathway in Inflammation. Cold Spring Harb. Perspect. Biol., 1(6), a001651-a001651. https://doi.org/10.1101/cshperspect.a001651Lee, G.-Y., Jeong, S.-Y., Lee, H.-R., y Oh, I.-H. (2019). Age-related differences in the bone marrow stem cell niche generate specialized microenvironments for the distinct regulation of normal hematopoietic and leukemia stem cells. Sci Rep, 9(1), 1007. https://doi.org/10.1038/s41598-018-36999-5Lemmon, M. A. y Schlessinger, J. (2010). Cell Signaling by Receptor Tyrosine Kinases. Cell, 141(7), 1117-1134. https://doi.org/10.1016/j.cell.2010.06.011Lerrer, S., Liubomirski, Y., Bott, A., Abnaof, K., Oren, N., Yousaf, A., Körner, C., Meshel, T., Wiemann, S., y Ben-Baruch, A. (2017). Co-Inflammatory Roles of TGFβ1 in the Presence of TNFα Drive a Pro-inflammatory Fate in Mesenchymal Stem Cells. Front Immunol, 8, 479. https://doi.org/10.3389/fimmu.2017.00479Lim, M., Pang, Y., Ma, S., Hao, S., Shi, H., Zheng, Y., Hua, C., Gu, X., Yang, F., Yuan, W., y Cheng, T. (2016). Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow. Leukemia, 30(1), 154-162. https://doi.org/10.1038/leu.2015.210Liu, W. . y Heckman, C. . (1998). The Sevenfold Way of PKC Regulation. Cell. Signal., 10(8), 529-542. https://doi.org/10.1016/S0898-6568(98)00012-6Loi, T. H., Dai, P., Carlin, S., Melo, J. V, y Ma, D. D. F. (2016). Pro-survival role of protein kinase C epsilon in Philadelphia chromosome positive acute leukemia. Leuk. Lymphoma, 57(2), 411-418. https://doi.org/10.3109/10428194.2015.1043545Lutzny, G., Kocher, T., Schmidt-Supprian, M., Rudelius, M., Klein-Hitpass, L., Finch, A. J., Dürig, J., Wagner, M., Haferlach, C., Kohlmann, A., Schnittger, S., Seifert, M., Wanninger, S., Zaborsky, N., Oostendorp, R., Ruland, J., Leitges, M., Kuhnt, T., Schäfer, Y., … Ringshausen, I. (2013). Protein Kinase C-β-Dependent Activation of NF-κB in Stromal Cells Is Indispensable for the Survival of Chronic Lymphocytic Leukemia B Cells In Vivo. Cancer Cell, 23(1), 77-92. https://doi.org/10.1016/j.ccr.2012.12.003Lwin, T., Hazlehurst, L. A., Li, Z., Dessureault, S., Sotomayor, E., Moscinski, L. C., Dalton, W. S., y Tao, J. (2007). Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-κB (RelB/p52) in non-Hodgkin’s lymphoma cells. Leukemia, 21(7), 1521-1531. https://doi.org/10.1038/sj.leu.2404723Macanas-Pirard, P., Quezada, T., Navarrete, L., Broekhuizen, R., Leisewitz, A., Nervi, B., y Ramírez, P. A. (2017). The CCL2/CCR2 axis affects transmigration and proliferation but not resistance to chemotherapy of acute myeloid leukemia cells. PLoS ONE, 12(1). https://doi.org/10.1371/journal.pone.0168888Macip, S., Igarashi, M., Berggren, P., Yu, J., Lee, S. W., y Aaronson, S. A. (2003). Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol. Cell. Biol. https://doi.org/10.1128/MCB.23.23.8576-8585.2003Mahindra, A., Hideshima, T., y Anderson, K. C. (2010). Multiple myeloma: Biology of the disease. En Blood Reviews (Vol. 24, Número SUPPL. 1). https://doi.org/10.1016/S0268-960X(10)70003-5Manabe, A., Coustan-Smith, E., Behm, F. G., Raimondi, S. C., y Campana, D. (1992). Bone marrow-derived stromal cells prevent apoptotic cell death in B-lineage acute lymphoblastic leukemia. Blood, 79(9), 2370-2377. http://www.ncbi.nlm.nih.gov/pubmed/1373973Manabe, A., Murti, K., Coustan-Smith, E., Kumagai, M., Behm, F., Raimondi, S., y Campana, D. (1994). Adhesion-dependent survival of normal and leukemic human B lymphoblasts on bone marrow stromal cells. Blood, 83(3), 758-766. https://doi.org/10.1182/blood.V83.3.758.bloodjournal833758Mangolini, M., Götte, F., Moore, A., Ammon, T., Oelsner, M., Lutzny-Geier, G., Klein-Hitpass, L., Williamson, J. C., Lehner, P. J., Dürig, J., Möllmann, M., Rásó-Barnett, L., Hughes, K., Santoro, A., Méndez-Ferrer, S., Oostendorp, R. A. J., Zimber-Strobl, U., Peschel, C., Hodson, D. J., … Ringshausen, I. (2018). Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia. Nat. Commun., 9(1), 3839. https://doi.org/10.1038/s41467-018-06069-5Mangolini, M. y Ringshausen, I. (2020). Bone Marrow Stromal Cells Drive Key Hallmarks of B Cell Malignancies. Int. J. Mol. Sci., 21(4), 1466. https://doi.org/10.3390/ijms21041466Marlein, C. R., Piddock, R. E., Mistry, J. J., Zaitseva, L., Hellmich, C., Horton, R. H., Zhou, Z., Auger, M. J., Bowles, K. M., y Rushworth, S. A. (2019). CD38-Driven Mitochondrial Trafficking Promotes Bioenergetic Plasticity in Multiple Myeloma. Cancer Research, 79(9), 2285-2297. https://doi.org/10.1158/0008-5472.CAN-18-0773Mas-Bargues, C., Sanz-Ros, J., Román-Domínguez, A., Inglés, M., Gimeno-Mallench, L., El Alami, M., Viña-Almunia, J., Gambini, J., Viña, J., y Borrás, C. (2019). Relevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine. Int. J. Mol. Sci., 20(5), 1195. https://doi.org/10.3390/ijms20051195Medina, D. J., Goodell, L., Glod, J., Gelinas, C., Rabson, A. B., y Strair, R. K. (2012). Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor B pathways. Haematologica, 97(8), 1255-1263. https://doi.org/10.3324/haematol.2011.040659Meggio, F., Deana, A. D., Ruzzene, M., Brunati, A. M., Cesaro, L., Guerra, B., Meyer, T., Mett, H., Fabbro, D., Furet, P., Dobrowolska, G., y Pinna, L. A. (1995). Different Susceptibility of Protein Kinases to Staurosporine Inhibition: Kinetic Studies and Molecular Bases for the Resistance of Protein Kinase CK2. Eur. j. biochem., 234(1). https://doi.org/10.1111/j.1432-1033.1995.317_c.xMinsalud y Colciencias. (2013). Guía de Práctica Clínica para la detección oportuna, diagnóstico y seguimiento de leucemia linfoide aguda y leucemia mieloide aguda en niños, niñas y adolescentes. En Centro Nacional de Investigacion en Evidencia y Tecnologia en Salud CINETS (Número 9).Miranda-Filho, A., Piñeros, M., Ferlay, J., Soerjomataram, I., Monnereau, A., y Bray, F. (2018). Epidemiological patterns of leukaemia in 184 countries: a population-based study. Lancet Haematol., 5(1), e14-e24. https://doi.org/10.1016/S2352-3026(17)30232-6Möricke, A., Reiter, A., Zimmermann, M., Gadner, H., Stanulla, M., Dördelmann, M., Löning, L., Beier, R., Ludwig, W. D., Ratei, R., Harbott, J., Boos, J., Mann, G., Niggli, F., Feldges, A., Henze, G., Welte, K., Beck, J. D., Klingebiel, T., … Schrappe, M. (2008). Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: Treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood, 111(9). https://doi.org/10.1182/blood-2007-09-112920Mullighan, C. G. (2013). Genomic Characterization of Childhood Acute Lymphoblastic Leukemia. Sem Hematol, 50(4), 314-324. https://doi.org/10.1053/j.seminhematol.2013.10.001Muto, T., Walker, C. S., Choi, K., Hueneman, K., Smith, M. A., Gul, Z., Garcia-Manero, G., Ma, A., Zheng, Y., y Starczynowski, D. T. (2020). Adaptive response to inflammation contributes to sustained myelopoiesis and confers a competitive advantage in myelodysplastic syndrome HSCs. Nat. Immunol., 21(5), 535-545. https://doi.org/10.1038/s41590-020-0663-zNakagawa, R., Soh, J. W., y Michie, A. M. (2006). Subversion of protein kinase Cα signaling in hematopoietic progenitor cells results in the generation of a B-cell chronic lymphocytic leukemia-like population in vivo. Cancer Research, 66(1). https://doi.org/10.1158/0008-5472.CAN-05-0841Nakagawa, R., Vukovic, M., Tarafdar, A., Cosimo, E., Dunn, K., McCaig, A. M., Holroyd, A., McClanahan, F., Ramsay, A. G., Gribben, J. G., y Michie, A. M. (2015). Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKCα subversion induces up-regulation of PKCβII expression in B lymphocytes. Haematologica, 100(4). https://doi.org/10.3324/haematol.2014.112276Nomellini, V., Brubaker, A. L., Mahbub, S., Palmer, J. L., Gomez, C. R., y Kovacs, E. J. (2012). Dysregulation of neutrophil CXCR2 and pulmonary endothelial ICAM-1 promotes age-related pulmonary inflammation. Aging Dis., 3(3).Oh, I.-H., Jeong, S.-Y., y Kim, J.-A. (2019). Normal and leukemic stem cell niche interactions. Curr Opin Hematol, 26(4), 249-257. https://doi.org/10.1097/MOH.0000000000000508Oliver, L., Hue, E., Séry, Q., Lafargue, A., Pecqueur, C., Paris, F., y Vallette, F. M. (2013). Differentiation-Related Response to DNA Breaks in Human Mesenchymal Stem Cells. Stem Cells, 31(4), 800-807. https://doi.org/10.1002/stem.1336Ortiz-Montero, P., Londoño-Vallejo, A., y Vernot, J.-P. (2017). Senescence-associated IL-6 and IL-8 cytokines induce a self- and cross-reinforced senescence/inflammatory milieu strengthening tumorigenic capabilities in the MCF-7 breast cancer cell line. Cell Commun Signal., 15(1), 17. https://doi.org/10.1186/s12964-017-0172-3Paggetti, J., Haderk, F., Seiffert, M., Janji, B., Distler, U., Ammerlaan, W., Kim, Y. J., Adam, J., Lichter, P., Solary, E., Berchem, G., y Moussay, E. (2015). Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. Blood, 126(9), 1106-1117. https://doi.org/10.1182/blood-2014-12-618025Pardo, C. y Cendales, R. (2015). Incidencia, mortalidad y prevalencia de cáncer en Colombia, 2007-2011. Primera edición. Bogotá. D.C. Instituto Nacional de Cancerología (Vol. 1).Park, E., Chen, J., Moore, A., Mangolini, M., Santoro, A., Boyd, J. R., Schjerven, H., Ecker, V., Buchner, M., Williamson, J. C., Lehner, P. J., Gasparoli, L., Williams, O., Bloehdorn, J., Stilgenbauer, S., Leitges, M., Egle, A., Schmidt-Supprian, M., Frietze, S., y Ringshausen, I. (2020). Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance. Sci. Transl. Med., 12(526), eaax9340. https://doi.org/10.1126/scitranslmed.aax9340Patel, V., Chen, L. S., Wierda, W. G., Balakrishnan, K., y Gandhi, V. (2014). Impact of bone marrow stromal cells on Bcl-2 family members in chronic lymphocytic leukemia. Leuk. Lymphoma, 55(4). https://doi.org/10.3109/10428194.2013.819573Peled, A., Klein, S., Beider, K., Burger, J. A., y Abraham, M. (2018). Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies. Cytokine, 109, 11-16. https://doi.org/10.1016/j.cyto.2018.02.020Perdomo-Arciniegas, A. M., Patarroyo, M. E., y Vernot, J.-P. (2008). Novel Chimeric Peptide Inhibits Protein Kinase C and Induces Apoptosis in Human Immune Cells. Int J Pept Res Ther., 14(1), 64-74. https://doi.org/10.1007/s10989-007-9118-8Pietras, K. y Östman, A. (2010). Hallmarks of cancer: Interactions with the tumor stroma. Exp. Cell Res., 316(8), 1324-1331. https://doi.org/10.1016/j.yexcr.2010.02.045Pleyer, L., Valent, P., y Greil, R. (2016). Mesenchymal stem and progenitor cells in normal and dysplastic hematopoiesis—Masters of survival and clonality? En International Journal of Molecular Sciences (Vol. 17, Número 7). https://doi.org/10.3390/ijms17071009Polak, R., de Rooij, B., Pieters, R., y den Boer, M. L. (2015). B-cell precursor acute lymphoblastic leukemia cells use tunneling nanotubes to orchestrate their microenvironment. Blood, 126(21), 2404-2414. https://doi.org/10.1182/blood-2015-03-634238Pui, C.-H. y Evans, W. E. (2006). Treatment of Acute Lymphoblastic Leukemia. N Engl J Med, 354(2), 166-178. https://doi.org/10.1056/NEJMra052603Quintarelli, C., De Angelis, B., Errichiello, S., Caruso, S., Esposito, N., Colavita, I., Raia, M., Pagliuca, S., Pugliese, N., Risitano, A. M., Picardi, M., Luciano, L., Saglio, G., Martinelli, G., y Pane, F. (2014). Selective strong synergism of Ruxolitinib and second generation tyrosine kinase inhibitors to overcome bone marrow stroma related drug resistance in chronic myelogenous leukemia. Leuk. Res., 38(2), 236-242. https://doi.org/10.1016/j.leukres.2013.11.006Raaijmakers, M. H. G. P., Mukherjee, S., Guo, S., Zhang, S., Kobayashi, T., Schoonmaker, J. A., Ebert, B. L., Al-Shahrour, F., Hasserjian, R. P., Scadden, E. O., Aung, Z., Matza, M., Merkenschlager, M., Lin, C., Rommens, J. M., y Scadden, D. T. (2010). Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature, 464(7290), 852-857. https://doi.org/10.1038/nature08851Raffaghello, L., Vacca, A., Pistoia, V., y Ribatti, D. (2015). Cancer associated fibroblasts in hematological malignancies. Oncotarget, 6(5), 2589-2603. https://doi.org/10.18632/oncotarget.2661Raposo, G. y Stoorvogel, W. (2013). Extracellular vesicles: Exosomes, microvesicles, and friends. Int. J. Cell Biol., 200(4), 373-383. https://doi.org/10.1083/jcb.201211138Redig, A. J. y Platanias, L. C. (2008). Protein kinase C signalling in leukemia. Leukemia & Lymphoma, 49(7), 1255-1262. https://doi.org/10.1080/10428190802007726Reikvam, H., Brenner, A. K., Hagen, K. M., Liseth, K., Skrede, S., Hatfield, K. J., y Bruserud, Ø. (2015). The cytokine-mediated crosstalk between primary human acute myeloid cells and mesenchymal stem cells alters the local cytokine network and the global gene expression profile of the mesenchymal cells. Stem Cell Res., 15(3), 530-541. https://doi.org/10.1016/j.scr.2015.09.008Reikvam, H., Fredly, H., Kittang, A., y Bruserud, Ø. (2013). The Possible Diagnostic and Prognostic Use of Systemic Chemokine Profiles in Clinical Medicine—The Experience in Acute Myeloid Leukemia from Disease Development and Diagnosis via Conventional Chemotherapy to Allogeneic Stem Cell Transplantation. Toxins, 5(2), 336-362. https://doi.org/10.3390/toxins5020336Ruiz-Aparicio, P. F., Vanegas, N.-D. P., Uribe, G. I., Ortiz-Montero, P., Cadavid-Cortés, C., Lagos, J., Flechas-Afanador, J., Linares-Ballesteros, A., y Vernot, J.-P. (2020). Dual Targeting of Stromal Cell Support and Leukemic Cell Growth by a Peptidic PKC Inhibitor Shows Effectiveness against B-ALL. Int. J. Mol. Sci., 21(10), 3705. https://doi.org/10.3390/ijms21103705Rustom, A., Saffrich, R., Markovic, I., Walther, P., y Gerdes, H. H. (2004). Nanotubular Highways for Intercellular Organelle Transport. Science, 303(5660). https://doi.org/10.1126/science.1093133Schepers, K., Pietras, E. M., Reynaud, D., Flach, J., Binnewies, M., Garg, T., Wagers, A. J., Hsiao, E. C., y Passegué, E. (2013). Myeloproliferative Neoplasia Remodels the Endosteal Bone Marrow Niche into a Self-Reinforcing Leukemic Niche. Cell Stem Cell, 13(3), 285-299. https://doi.org/10.1016/j.stem.2013.06.009Schinke, C., Giricz, O., Li, W., Shastri, A., Gordon, S., Barreyro, L., Bhagat, T., Bhattacharyya, S., Ramachandra, N., Bartenstein, M., Pellagatti, A., Boultwood, J., Wickrema, A., Yu, Y., Will, B., Wei, S., Steidl, U., y Verma, A. (2015). IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells. Blood, 125(20), 3144-3152. https://doi.org/10.1182/blood-2015-01-621631Schultz, K. R., Pullen, D. J., Sather, H. N., Shuster, J. J., Devidas, M., Borowitz, M. J., Carroll, A. J., Heerema, N. A., Rubnitz, J. E., Loh, M. L., Raetz, E. A., Winick, N. J., Hunger, S. P., Carroll, W. L., Gaynon, P. S., y Camitta, B. M. (2007). Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG). Blood, 109(3), 926-935. https://doi.org/10.1182/blood-2006-01-024729Severe, N., Karabacak, N. M., Gustafsson, K., Baryawno, N., Courties, G., Kfoury, Y., Kokkaliaris, K. D., Rhee, C., Lee, D., Scadden, E. W., Garcia-Robledo, J. E., Brouse, T., Nahrendorf, M., Toner, M., y Scadden, D. T. (2019). Stress-Induced Changes in Bone Marrow Stromal Cell Populations Revealed through Single-Cell Protein Expression Mapping. Cell Stem Cell, 25(4), 570-583.e7. https://doi.org/10.1016/j.stem.2019.06.003Shain, K. H., Yarde, D. N., Meads, M. B., Huang, M., Jove, R., Hazlehurst, L. A., y Dalton, W. S. (2009). β1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: Implications for microenvironment influence on tumor survival and proliferation. Cancer Res., 69(3). https://doi.org/10.1158/0008-5472.CAN-08-2419Shchemelinin, I., Sefc, L., y Necas, E. (2006). Protein kinases, their function and implication in cancer and other diseases. Folia biologica, 52(3), 81-100. http://www.ncbi.nlm.nih.gov/pubmed/17089919Shiga, K., Hara, M., Nagasaki, T., Sato, T., Takahashi, H., y Takeyama, H. (2015). Cancer-associated fibroblasts: Their characteristics and their roles in tumor growth. En Cancers (Vol. 7, Número 4). https://doi.org/10.3390/cancers7040902Shih, V. F.-S., Tsui, R., Caldwell, A., y Hoffmann, A. (2011). A single NFκB system for both canonical and non-canonical signaling. Cell Res., 21(1), 86-102. https://doi.org/10.1038/cr.2010.161Steinberg, S. F. (2008). Structural Basis of Protein Kinase C Isoform Function. Physiol. Rev., 88(4), 1341-1378. https://doi.org/10.1152/physrev.00034.2007Strzyz, P. (2019). The unusual SASPects. Nat. Rev. Mol. Cell Biol., 20(4), 195-195. https://doi.org/10.1038/s41580-019-0111-9Sun, X. y Kaufman, P. D. (2018). Ki-67: more than a proliferation marker. En Chromosoma. https://doi.org/10.1007/s00412-018-0659-8Takami, M., Katayama, K., Noguchi, K., y Sugimoto, Y. (2018). Protein kinase C alpha-mediated phosphorylation of PIM-1L promotes the survival and proliferation of acute myeloid leukemia cells. Biochemical and Biophysical Research Communications, 503(3). https://doi.org/10.1016/j.bbrc.2018.07.049Tamaoki, T., Nomoto, H., Takahashi, I., Kato, Y., Morimoto, M., y Tomita, F. (1986). Staurosporine, a potent inhibitor of phospholipidCa++dependent protein kinase. Biochem. Biophys. Res. Commun., 135(2), 397-402. https://doi.org/10.1016/0006-291X(86)90008-2Tasian, S. K. y Loh, M. L. (2011). Understanding the biology of CRLF2-overexpressing acute lymphoblastic leukemia. Crit Rev Oncog. https://doi.org/10.1615/CritRevOncog.v16.i1-2.30Teicher, B. A. y Fricker, S. P. (2010). CXCL12 (SDF-1)/CXCR4 pathway in cancer. En Clinical Cancer Research (Vol. 16, Número 11). https://doi.org/10.1158/1078-0432.CCR-09-2329Tobler, A., Moser, B., Dewald, B., Geiser, T., Studer, H., Baggiolini, M., y Fey, M. (1993). Constitutive expression of interleukin-8 and its receptor in human myeloid and lymphoid leukemia. Blood, 82(8), 2517-2525. https://doi.org/10.1182/blood.V82.8.2517.bloodjournal8282517Traer, E., MacKenzie, R., Snead, J., Agarwal, A., Eiring, A. M., O’Hare, T., Druker, B. J., y Deininger, M. W. (2012). Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors. Leukemia, 26(5), 1140-1143. https://doi.org/10.1038/leu.2011.325Turinetto, V., Vitale, E., y Giachino, C. (2016). Senescence in Human Mesenchymal Stem Cells: Functional Changes and Implications in Stem Cell-Based Therapy. Int. J. Mol. Sci., 17(7), 1164. https://doi.org/10.3390/ijms17071164Van Etten, R. A. (2007). Aberrant cytokine signaling in leukemia. Oncogene, 26(47), 6738-6749. https://doi.org/10.1038/sj.onc.1210758Vanegas, N.-D. P. y Vernot, J.-P. (2017). Loss of quiescence and self-renewal capacity of hematopoietic stem cell in an in vitro leukemic niche. Exp. Hematol. Oncol., 6(1), 2. https://doi.org/10.1186/s40164-016-0062-1Vernot, J.-P., Bonilla, X., Rodriguez-Pardo, V., y Vanegas, N.-D. P. (2017). Phenotypic and Functional Alterations of Hematopoietic Stem and Progenitor Cells in an In Vitro Leukemia-Induced Microenvironment. Int. J. Mol. Sci., 18(2), 199. https://doi.org/10.3390/ijms18020199Vilchis-Ordoñez, A., Contreras-Quiroz, A., Vadillo, E., Dorantes-Acosta, E., Reyes-López, A., Quintela-Nuñez Del Prado, H. M., Venegas-Vázquez, J., Mayani, H., Ortiz-Navarrete, V., López-Martínez, B., y Pelayo, R. (2015). Bone marrow cells in acute lymphoblastic leukemia create a proinflammatory microenvironment influencing normal hematopoietic differentiation fates. Biomed Res. Int. https://doi.org/10.1155/2015/386165Vitale, I., Manic, G., De Maria, R., Kroemer, G., y Galluzzi, L. (2017). DNA Damage in Stem Cells. Mol Cell, 66(3), 306-319. https://doi.org/10.1016/j.molcel.2017.04.006Wagner, W., Horn, P., Castoldi, M., Diehlmann, A., Bork, S., Saffrich, R., Benes, V., Blake, J., Pfister, S., Eckstein, V., y Ho, A. D. (2008). Replicative Senescence of Mesenchymal Stem Cells: A Continuous and Organized Process. PLoS ONE, 3(5), e2213. https://doi.org/10.1371/journal.pone.0002213Walkley, C. R., Olsen, G. H., Dworkin, S., Fabb, S. A., Swann, J., McArthur, G. A., Westmoreland, S. V., Chambon, P., Scadden, D. T., y Purton, L. E. (2007). A Microenvironment-Induced Myeloproliferative Syndrome Caused by Retinoic Acid Receptor γ Deficiency. Cell, 129(6), 1097-1110. https://doi.org/10.1016/j.cell.2007.05.014Wallace, S. R., Oken, M. M., Lunetta, K. L., Panoskaltsis-Mortari, A., y Masellis, A. M. (2001). Abnormalities of bone marrow mesenchymal cells in multiple myeloma patients. Cancer, 91(7), 1219-1230. https://doi.org/10.1002/1097-0142(20010401)91:7<1219::AID-CNCR1122>3.0.CO;2-1Weisberg, E., Azab, A. K., Manley, P. W., Kung, A. L., Christie, A. L., Bronson, R., Ghobrial, I. M., y Griffin, J. D. (2012). Inhibition of CXCR4 in CML cells disrupts their interaction with the bone marrow microenvironment and sensitizes them to nilotinib. Leukemia, 26(5), 985-990. https://doi.org/10.1038/leu.2011.360Windisch, R., Pirschtat, N., Kellner, C., Chen-Wichmann, L., Lausen, J., Humpe, A., Krause, D., y Wichmann, C. (2019). Oncogenic Deregulation of Cell Adhesion Molecules in Leukemia. Cancers, 11(3), 311. https://doi.org/10.3390/cancers11030311Xu, S., De Veirman, K., De Becker, A., Vanderkerken, K., y Van Riet, I. (2018). Mesenchymal stem cells in multiple myeloma: a therapeutical tool or target? Leukemia, 32(7), 1500-1514. https://doi.org/10.1038/s41375-018-0061-9Zambetti, N. A., Ping, Z., Chen, S., Kenswil, K. J. G., Mylona, M. A., Sanders, M. A., Hoogenboezem, R. M., Bindels, E. M. J., Adisty, M. N., Van Strien, P. M. H., van der Leije, C. S., Westers, T. M., Cremers, E. M. P., Milanese, C., Mastroberardino, P. G., van Leeuwen, J. P. T. M., van der Eerden, B. C. J., Touw, I. P., Kuijpers, T. W., … Raaijmakers, M. H. G. P. (2016). Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia. Cell Stem Cell, 19(5). https://doi.org/10.1016/j.stem.2016.08.021Zhang, B., Ho, Y. W., Huang, Q., Maeda, T., Lin, A., Lee, S., Hair, A., Holyoake, T. L., Huettner, C., y Bhatia, R. (2012). Altered Microenvironmental Regulation of Leukemic and Normal Stem Cells in Chronic Myelogenous Leukemia. Cancer Cell, 21(4), 577-592. https://doi.org/10.1016/j.ccr.2012.02.018Zhang, B., Li, M., McDonald, T., Holyoake, T. L., Moon, R. T., Campana, D., Shultz, L., y Bhatia, R. (2013). Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt–β-catenin signaling. Blood, 121(10), 1824-1838. https://doi.org/10.1182/blood-2012-02-412890Zhao, Z.-G., Liang, Y., Li, K., Li, W.-M., Li, Q.-B., Chen, Z.-C., y Zou, P. (2007). Phenotypic and Functional Comparison of Mesenchymal Stem Cells Derived from the Bone Marrow of Normal Adults and Patients with Hematologic Malignant Diseases. Stem Cells Dev., 16(4), 637-648. https://doi.org/10.1089/scd.2007.0008Zheng, Y., Tu, C., Zhang, J., y Wang, J. (2019). Inhibition of multiple myeloma‑derived exosomes uptake suppresses the functional response in bone marrow stromal cell. Int. J. Oncol., 54(3). https://doi.org/10.3892/ijo.2019.4685Zhou, D., Shao, L., y Spitz, D. R. (2014). Reactive Oxygen Species in Normal and Tumor Stem Cells. En Adv. Cancer Res. (pp. 1-67). https://doi.org/10.1016/B978-0-12-420117-0.00001-3Ministerio de Ciencia, Tecnología e Innovación Contrato No. 58257InvestigadoresLICENSElicense.txtlicense.txttext/plain; charset=utf-83964https://repositorio.unal.edu.co/bitstream/unal/80304/1/license.txtcccfe52f796b7c63423298c2d3365fc6MD51ORIGINAL1010195476.2021.pdf1010195476.2021.pdfDoctorado en Ciencias Biomédicasapplication/pdf141635769https://repositorio.unal.edu.co/bitstream/unal/80304/2/1010195476.2021.pdf32987381d74b1f9fc82beb3120db91baMD52THUMBNAIL1010195476.2021.pdf.jpg1010195476.2021.pdf.jpgGenerated Thumbnailimage/jpeg6059https://repositorio.unal.edu.co/bitstream/unal/80304/3/1010195476.2021.pdf.jpg840841a8dda2a2b1fa8cc3a5b45f1fe8MD53unal/80304oai:repositorio.unal.edu.co:unal/803042023-07-28 23:03:51.1Repositorio Institucional Universidad Nacional de Colombiarepositorio_nal@unal.edu.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 |