Relación entre la expresión de ID1 e ID3 y el microambiente tumoral inmune de la médula ósea en adultos con leucemia linfoblástica aguda de células precursoras B
Ilustraciones a color, diagramas
- Autores:
-
Poveda Garavito, Jenny Nathaly
- Tipo de recurso:
- Fecha de publicación:
- 2024
- Institución:
- Universidad Nacional de Colombia
- Repositorio:
- Universidad Nacional de Colombia
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.unal.edu.co:unal/86560
- Palabra clave:
- 610 - Medicina y salud
Sistema Inmunológico
Médula ósea
Monitorización Inmunológica
Immune System
Bone Marrow
Monitoring, Immunologic
Leucemia linfoblástica
Lymphoblastic leukemia
Leucemia linfoblástica aguda de células B precursoras
Sistema inmunitario
Médula ósea
Microambiente
Inmunovigilancia
ID1
ID3
- Rights
- openAccess
- License
- Atribución-NoComercial 4.0 Internacional
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oai:repositorio.unal.edu.co:unal/86560 |
network_acronym_str |
UNACIONAL2 |
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Universidad Nacional de Colombia |
repository_id_str |
|
dc.title.spa.fl_str_mv |
Relación entre la expresión de ID1 e ID3 y el microambiente tumoral inmune de la médula ósea en adultos con leucemia linfoblástica aguda de células precursoras B |
dc.title.translated.none.fl_str_mv |
Relationship between ID1 and ID3 expression and the bone marrow immune tumor microenvironment in adults with B precursor cell acute lymphoblastic leukemia |
title |
Relación entre la expresión de ID1 e ID3 y el microambiente tumoral inmune de la médula ósea en adultos con leucemia linfoblástica aguda de células precursoras B |
spellingShingle |
Relación entre la expresión de ID1 e ID3 y el microambiente tumoral inmune de la médula ósea en adultos con leucemia linfoblástica aguda de células precursoras B 610 - Medicina y salud Sistema Inmunológico Médula ósea Monitorización Inmunológica Immune System Bone Marrow Monitoring, Immunologic Leucemia linfoblástica Lymphoblastic leukemia Leucemia linfoblástica aguda de células B precursoras Sistema inmunitario Médula ósea Microambiente Inmunovigilancia ID1 ID3 |
title_short |
Relación entre la expresión de ID1 e ID3 y el microambiente tumoral inmune de la médula ósea en adultos con leucemia linfoblástica aguda de células precursoras B |
title_full |
Relación entre la expresión de ID1 e ID3 y el microambiente tumoral inmune de la médula ósea en adultos con leucemia linfoblástica aguda de células precursoras B |
title_fullStr |
Relación entre la expresión de ID1 e ID3 y el microambiente tumoral inmune de la médula ósea en adultos con leucemia linfoblástica aguda de células precursoras B |
title_full_unstemmed |
Relación entre la expresión de ID1 e ID3 y el microambiente tumoral inmune de la médula ósea en adultos con leucemia linfoblástica aguda de células precursoras B |
title_sort |
Relación entre la expresión de ID1 e ID3 y el microambiente tumoral inmune de la médula ósea en adultos con leucemia linfoblástica aguda de células precursoras B |
dc.creator.fl_str_mv |
Poveda Garavito, Jenny Nathaly |
dc.contributor.advisor.none.fl_str_mv |
Combita Rojas, Alba Lucía Orozco Castaño, Carlos Alberto |
dc.contributor.author.none.fl_str_mv |
Poveda Garavito, Jenny Nathaly |
dc.contributor.researchgroup.spa.fl_str_mv |
Grupo de Investigación en Biología del Cáncer Grupo de Investigación Traslacional en Oncología |
dc.contributor.orcid.spa.fl_str_mv |
0009-0000-6605-873X Poveda Garavito, Jenny Nathaly [0009-0000-6605-873X] |
dc.contributor.cvlac.spa.fl_str_mv |
Poveda Garavito, Jenny Nathaly [0000074526] |
dc.contributor.researchgate.spa.fl_str_mv |
https://www.researchgate.net/profile/Jenny-Poveda-Garavito |
dc.subject.ddc.spa.fl_str_mv |
610 - Medicina y salud |
topic |
610 - Medicina y salud Sistema Inmunológico Médula ósea Monitorización Inmunológica Immune System Bone Marrow Monitoring, Immunologic Leucemia linfoblástica Lymphoblastic leukemia Leucemia linfoblástica aguda de células B precursoras Sistema inmunitario Médula ósea Microambiente Inmunovigilancia ID1 ID3 |
dc.subject.other.spa.fl_str_mv |
Sistema Inmunológico Médula ósea Monitorización Inmunológica |
dc.subject.other.eng.fl_str_mv |
Immune System Bone Marrow Monitoring, Immunologic |
dc.subject.lemb.spa.fl_str_mv |
Leucemia linfoblástica |
dc.subject.lemb.eng.fl_str_mv |
Lymphoblastic leukemia |
dc.subject.proposal.spa.fl_str_mv |
Leucemia linfoblástica aguda de células B precursoras Sistema inmunitario Médula ósea Microambiente Inmunovigilancia |
dc.subject.proposal.none.fl_str_mv |
ID1 ID3 |
description |
Ilustraciones a color, diagramas |
publishDate |
2024 |
dc.date.accessioned.none.fl_str_mv |
2024-07-18T15:11:19Z |
dc.date.available.none.fl_str_mv |
2024-07-18T15:11:19Z |
dc.date.issued.none.fl_str_mv |
2024-05-08 |
dc.type.spa.fl_str_mv |
Trabajo de grado - Maestría |
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 |
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/86560 |
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/86560 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 |
1. Richard-Carpentier G, Kantarjian H, Jabbour E. Recent Advances in Adult Acute Lymphoblastic Leukemia. Curr Hematol Malig Rep. 2019 2. Roberts KG, Mullighan CG. The Biology of B-Progenitor Acute Lymphoblastic Leukemia. Cold Spring Harb Perspect Med [Internet]. 2020 Jul 1 [cited 2023 Jan 1];10(7):1–22. Available from: https://pubmed.ncbi.nlm.nih.gov/31653664/ 3. Felipe Combariza J, Casas CP, Rodriguez M. Rev Colomb CanCeRol 2007;11(2):92-100 93. 4. Chiarini F, Lonetti A, Evangelisti C, Buontempo F, Orsini E, Evangelisti C, et al. Advances in understanding the acute lymphoblastic leukemia bone marrow microenvironment: From biology to therapeutic targeting. Biochim Biophys Acta Mol Cell Res [Internet]. 2016;1863(3):449–63. Available from: http://dx.doi.org/10.1016/j.bbamcr.2015.08.015 5. Cruz-Rodriguez N, Combita AL, Enciso LJ, Raney LF, Pinzon PL, Lozano OC, et al. Prognostic stratification improvement by integrating ID1/ID3/IGJ gene expression signature and immunophenotypic profile in adult patients with B-ALL. Journal of Experimental and Clinical Cancer Research. 2017;36(1):1–12. 6. Roschger C, Cabrele C. The Id-protein family in developmental and cancer-associated pathways Fritz Aberger. Cell Communication and Signaling. 2017;15(1):1–26. 7. Wang LH, Baker NE. E-proteins and ID-proteins: Helix-loop-helix partners in development and disease. Dev Cell [Internet]. 2015 Nov 11 [cited 2023 Dec 12];35(3):269. Available from: /pmc/articles/PMC4684411/ 8. Perk J, Iavarone A, Benezra R. Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer. 2005;5(8):603–14. 9. Roberts EC, Deed RW, Inoue T, Norton JD, Sharrocks AD. Id Helix-Loop-Helix Proteins Antagonize Pax Transcription Factor Activity by Inhibiting DNA Binding. Mol Cell Biol. 2001 Jan 15;21(2):524–33. 10. Ruzinova MB, Benezra R. Id proteins in development , cell cycle and cancer. 2003;13(8):410–8. 11. Ling MT, Wang X, Zhang X, Wong YC. The multiple roles of Id-1 in cancer progression. Differentiation. 2006;74(9–10):481–7. 12. Nakatsukasa H, Zhang D, Maruyama T, Chen H, Cui K, Ishikawa M, et al. The DNA-binding inhibitor Id3 regulates IL-9 production in CD4 + T cells. Nat Immunol. 2015;16(10):1077–84. 13. Melief J, Pico de Coaña Y, Maas R, Fennemann FL, Wolodarski M, Hansson J, et al. High expression of ID1 in monocytes is strongly associated with phenotypic and functional MDSC markers in advanced melanoma. Cancer Immunology, Immunotherapy. 2020;69(4):513–22. 14. Ma C, Witkowski MT, Harris J, Dolgalev I, Sreeram S, Qian W, et al. Leukemia-on-a-chip: Dissecting the chemoresistance mechanisms in B cell acute lymphoblastic leukemia bone marrow niche. Sci Adv. 2020 Oct 28;6(44). 15. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394–424. 16. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019 Apr 15;144(8):1941–53. 17. Hoelzer D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C. Acute lymphoblastic leukaemia in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2016;27:v69–82. 18. Schwab C, Harrison CJ. Advances in B-cell Precursor Acute Lymphoblastic Leukemia Genomics. Hemasphere. 2018;1. 19. Paul S, Kantarjian H, Jabbour EJ. Adult Acute Lymphoblastic Leukemia. Vol. 91, Mayo Clinic Proceedings. Elsevier Ltd; 2016. p. 1645–66. 20. Papaspyridonos M, Matei I, Huang Y, Andre R, Brazier-mitouart H, Waite JC, et al. Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation. 2015; 21. Gloury R, Zotos D, Zuidscherwoude M, Masson F, Liao Y, Hasbold J, et al. Dynamic changes in Id3 and E-protein activity orchestrate germinal center and plasma cell development. Journal of Experimental Medicine. 2016;213(6):1095–111. 22. Lasorella A, Benezra R, Iavarone A. The ID proteins: Master regulators of cancer stem cells and tumour aggressiveness. Nat Rev Cancer. 2014;14(2):77–91. 23. Stankovic T, Marston E. MOLECULAR MECHANISMS INVOLVED IN CHEMORESISTANCE IN PAEDIATRIC ACUTE LYMPHOBLASTIC LEUKAEMIA. 2008;136:187–92. 24. Passaro D, Quang CT, Ghysdael J. Microenvironmental cues for T-cell acute lymphoblastic leukemia development. Immunol Rev. 2016;271(1):156–72. 25. Höpken UE, Rehm A. Targeting the Tumor Microenvironment of Leukemia and Lymphoma. Trends Cancer. 2019;5(6):351–64. 26. Houshmand M, Blanco TM, Circosta P, Yazdi N, Kazemi A, Saglio G, et al. Bone marrow microenvironment: The guardian of leukemia stem cells. Vol. 11, World Journal of Stem Cells. Baishideng Publishing Group Co; 2019. p. 476–90. 27. Rabe JL, Gardner L, Hunter R, Fonseca JA, Dougan J, Gearheart CM, et al. IL12 abrogates calcineurin-dependent immune evasion during leukemia progression. Cancer Res. 2019;79(14):3702–13. 28. Hunter R, Imbach KJ, Zhou C, Dougan J, Hamilton JAG, Chen KZ, et al. B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12. Scientific Reports 2022 12:1. 2022 Jul 13;12(1):1–13. 29. Malard F, Mohty M. Seminar Acute lymphoblastic leukaemia. The Lancet. 2020;395(10230):1146–62. 30. Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. The Lancet. 2013;381(9881):1943–55. 31. Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505(7483):327–34. 32. Hagman J. Transcriptional Regulation of Early B Cell Development. Second Edi. Molecular Biology of B Cells: Second Edition. Elsevier Ltd; 2015. 35–53 p. 33. Engel I, Murre C. The function of E- and ID proteins in lymphocyte development. Nat Rev Immunol. 2001;1(3):193–9. 34. Loghavi S, Kutok JL, Jorgensen JL. B-acute lymphoblastic leukemia/lymphoblastic lymphoma. Am J Clin Pathol. 2015;144(3):393–410. 35. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017;7(6):e577. 36. Cobaleda C, Sánchez-García I. B-cell acute lymphoblastic leukaemia: Towards understanding its cellular origin. BioEssays. 2009;31(6):600–9. 37. Iacobucci I, Mullighan CG. Genetic basis of acute lymphoblastic leukemia. Journal of Clinical Oncology. 2017;35(9):975–83. 38. Faderl S, O’Brien S, Pui CH, Stock W, Wetzler M, Hoelzer D, et al. Adult acute lymphoblastic leukemia: Concepts and strategies. Cancer. 2010;116(5):1165–76. 39. Sas V, Moisoiu V, Teodorescu P, Tranca S, Pop L, Iluta S, et al. Approach to the Adult Acute Lymphoblastic Leukemia Patient. J Clin Med. 2019;8(8):1175. 40. Bassan R, Bourquin JP, DeAngelo DJ, Chiaretti S. New approaches to the management of adult acute lymphoblastic leukemia. Journal of Clinical Oncology. 2018;36(35):3504–19. 41. Muffly LS, Reizine N, Stock W. Management of acute lymphoblastic leukemia in young adults. Clinical Advances in Hematology and Oncology. 2018;16(2):138–46. 42. Narayanan S, Shami PJ. Treatment of acute lymphoblastic leukemia in adults. Crit Rev Oncol Hematol. 2012;81(1):94–102. 43. Malouf C, Ottersbach K. Molecular processes involved in B cell acute lymphoblastic leukaemia. Cellular and Molecular Life Sciences. 2018;75(3):417–46. 44. Rafei H, Kantarjian HM, Jabbour EJ. Recent advances in the treatment of acute lymphoblastic leukemia. Leuk Lymphoma. 2019;60(11):2606–21. 45. Hoelzer D, Bassan R, Boissel N, Roddie C, Ribera JM, Jerkeman M. ESMO Clinical Practice Guideline interim update on the use of targeted therapy in acute lymphoblastic leukaemia. Annals of Oncology [Internet]. 2023 Oct [cited 2023 Dec 4];0(0). Available from: http://www.annalsofoncology.org/article/S0923753423040097/fulltext 46. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. New England Journal of Medicine. 2017 Mar 2;376(9):836–47. 47. Cruz-Rodriguez N, Combita AL, Enciso LJ, Quijano SM, Pinzon PL, Lozano OC, et al. High expression of ID family and IGJ genes signature as predictor of low induction treatment response and worst survival in adult Hispanic patients with B-Acute lymphoblastic leukemia. Journal of Experimental and Clinical Cancer Research. 2016;35(1):1–14. 48. Mami N Ben, Mohty M, Chambost H, Gaugler B, Olive D. Blood dendritic cells in patients with acute lymphoblastic leukaemia. Br J Haematol. 2004 Jul;126(1):77–80. 49. Liu C, Wang HC, Yu S, Jin R, Tang H, Liu YF, et al. Id1 Expression Promotes T Regulatory Cell Differentiation by Facilitating TCR Costimulation. The Journal of Immunology. 2014;193(2):663–72. 50. Yuen HF, Chan YP, Chan KK, Chu YY, Wong MLY, Law SYK, et al. Id-1 and Id-2 are markers for metastasis and prognosis in oesophageal squamous cell carcinoma. Br J Cancer. 2007;97(10):1409–15. 51. Nair R, Teo WS, Mittal V, Swarbrick A. ID Proteins Regulate Diverse Aspects of Cancer Progression and Provide Novel Therapeutic Opportunities. 2014;22(8):1407–15. 52. Weiler S, Ademokun JA, Norton JD. ID helix-loop-helix proteins as determinants of cell survival in B-cell chronic lymphocytic leukemia cells in vitro. 2015;1–20. 53. Zebedee Z, Hara E. Id proteins in cell cycle control and cellular senescence. Oncogene. 2001;20(58 REV. ISS. 8):8317–25. 54. Mellman I, Chen DS, Powles T, Turley SJ. The cancer-immunity cycle: Indication, genotype, and immunotype. Immunity. 2023 Oct 10;56(10):2188–205. 55. Roy S, Zhuang Y. Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells. Vol. 12, Frontiers of Medicine. Higher Education Press; 2018. p. 374–86. 56. Witkowski MT, Dolgalev I, Evensen NA, Tsirigos A, Carroll WL. Article Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia. Cancer Cell. 2020;37(6):867-882.e12. 57. Anderson D, Skut P, Hughes AM, Ferrari E, Tickner J, Xu J, et al. The bone marrow microenvironment of pre B acute lymphoblastic leukemia at single cell resolution. Sci Rep. 2020;1–14. 58. Méndez-Ferrer S, Bonnet D, Steensma DP, Hasserjian RP, Ghobrial IM, Gribben JG, et al. Bone marrow niches in haematological malignancies. Nat Rev Cancer. 2020; 59. Forte D, Krause DS, Andreeff M, Bonnet D, Méndez-Ferrer S. Updates on the hematologic tumor microenvironment and its therapeutic targeting. Haematologica. 2019;104(10):1928–34. 60. Man Y, Yao X, Yang T, Wang Y. Hematopoietic Stem Cell Niche During Homeostasis, Malignancy, and Bone Marrow Transplantation. Front Cell Dev Biol. 2021;9(January):1–11. 61. Meyer LK, Hermiston ML. The bone marrow microenvironment as a mediator of chemoresistance in acute lymphoblastic leukemia. 2019;1–14. 62. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93–106. 63. Reagan MR, Rosen CJ. Navigating the bone marrow niche: Translational insights and cancer-driven dysfunction. Nat Rev Rheumatol. 2016;12(3):154–68. 64. Zhao E, Xu H, Wang L, Kryczek I, Wu K, Hu Y, et al. Bone marrow and the control of immunity. 2012;(July 2011):11–9. 65. Mercier FE, Ragu C, Scadden DT. The bone marrow at the crossroads of blood and immunity. Nat Rev Immunol. 2012;12(1):49–60. 66. Riether C, Schürch CM, Ochsenbein AF. Regulation of hematopoietic and leukemic stem cells by the immune system. Cell Death Differ. 2015;22(2):187–98. 67. Autio M, Leivonen S katri, Brück O, Mustjoki S. Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma. 2021;106(3). 68. Fujisaki J, Wu J, Carlson AL, Silberstein L, Putheti P, Larocca R, et al. In vivo imaging of T reg cells providing immune privilege to the haematopoietic stem-cell niche. Nature. 2011;474(7350):216–20. 69. Shang S, Yang C, Chen F, Xiang R shen, Zhang H, Dai S yuan, et al. ID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer. Nat Commun. 2023;14(1). 70. Prabhu S, Ignatova A, Park ST, Sun XH. Regulation of the expression of cyclin-dependent kinase inhibitor p21 by E2A and Id proteins. Mol Cell Biol. 1997 Oct 1;17(10):5888. 71. Pan L, Sato S, Frederick JP, Sun XH, Zhuang Y. Impaired Immune Responses and B-Cell Proliferation in Mice Lacking the Id3 Gene. Mol Cell Biol. 1999;19(9):5969–80. 72. Zhao Q, Wang Y, Yu D, Leng JY, Zhao Y, Chu M, et al. Comprehensive analysis of ID genes reveals the clinical and prognostic value of ID3 expression in acute myeloid leukemia using bioinformatics identification and experimental validation. BMC Cancer. 2022;22(1):1–12. 74. Castañon E, Bosch-Barrera J, López I, Collado V, Moreno M, López-Picazo JM, et al. Id1 and Id3 co-expression correlates with clinical outcome in stage III-N2 non-small cell lung cancer patients treated with definitive chemoradiotherapy. J Transl Med. 2013 Jan 11;11(1):1–8. 75. O’Brien CA, Kreso A, Ryan P, Hermans KG, Gibson L, Wang Y, et al. ID1 and ID3 Regulate the Self-Renewal Capacity of Human Colon Cancer-Initiating Cells through p21. Cancer Cell. 2012 Jun 12;21(6):777–92. 76. Liu Y feng, Chen Y ying, He Y yi, Wang J yi, Yang J ping, Zhong S ling, et al. Expansion and activation of granulocytic, myeloid-derived suppressor cells in childhood precursor B cell acute lymphoblastic leukemia. J Leukoc Biol. 2017;102(2):449–58. 77. Song JX, Wen Y, Li RW, Dong T, Tang YF, Zhang JJ, et al. Phenotypic characterization of macrophages in the BMB sample of human acute leukemia. Ann Hematol. 2020;99(3):539–47. 78. Zhang Z, Liu S, Zhang B, Qiao L, Zhang Y, Zhang Y. T Cell Dysfunction and Exhaustion in Cancer. 2020;8(February). 79. Jin Y, Hu P, Sun H, Yang C, Zhai J, Wang Y, et al. Expression of Id3 represses exhaustion of anti-tumor CD8 T cells in liver cancer. Mol Immunol. 2022 Apr 1;144:117–26. 80. Lipp JJ, Wang L, Yang H, Yao F, Harrer N, Müller S, et al. Functional and molecular characterization of PD1+ tumor-infiltrating lymphocytes from lung cancer patients. Oncoimmunology. 2022 Dec 31;11(1). 81. Rauch KS, Hils M, Lupar E, Minguet S, Sigvardsson M, Rottenberg ME, et al. Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a Transcriptional Network of E47, Spi-B, and SOCS3. Cell Rep. 2016;17(11):2827–36. 82. Xue G, Zheng N, Fang J, Jin G, Li X, Dotti G, et al. Adoptive cell therapy with tumor-specific Th9 cells induces viral mimicry to eliminate antigen-loss-variant tumor cells. Cancer Cell. 2021 Dec 13;39(12):1610-1622.e9. 83. Lustfeld I, Ahlmann M. High Proportions of CD4 + T Cells among Residual Bone Marrow T Cells in Childhood Acute Lymphoblastic Leukemia Are Associated with Favorable Early Responses. 2014;28–36. 84. Salem ML, El-Shanshory MR, Abdou SH, Attia MS, Sobhy SM, Zidan MF, et al. Chemotherapy alters the increased numbers of myeloid-derived suppressor and regulatory T cells in children with acute lymphoblastic leukemia. Immunopharmacol Immunotoxicol. 2018;40(2):158–67. 85. El-maadawy EA, Elshal MF, Bakry RM, Moussa MM, El-Naby SH, Talaat RM. Regulation of CD4+CD25+FOXP3+ cells in Pediatric Acute Lymphoblastic Leukemia (ALL): Implication of cytokines and miRNAs. Mol Immunol. 2020;124(March):1–8. 86. Niedźwiecki M, Budziło O, Zieliński M, Adamkiewicz-Drożyńska E, Maciejka-Kembłowska L, Szczepański T, et al. CD4+CD25highCD127low/−FoxP3+ Regulatory T Cell Subpopulations in the Bone Marrow and Peripheral Blood of Children with ALL: Brief Report. J Immunol Res. 2018;2018. 87. Wu CP, Qing X, Wu CY, Zhu H, Zhou HY. Immunophenotype and increased presence of CD4 +CD25 + regulatory T cells in patients with acute lymphoblastic leukemia. Oncol Lett. 2012;3(2):421–4. 88. Liu SX, Xiao HR, Wang GB, Chen XW, Li CG, Mai HR, et al. Preliminary investigation on the abnormal mechanism of cd4+foxp3+cd25high regulatory t cells in pediatric b-cell acute lymphoblastic leukemia. Exp Ther Med. 2018;16(2):1433–41. 89. Idris SZ, Hassan N, Lee LJ, Md Noor S, Osman R, Abdul-Jalil M, et al. Increased regulatory T cells in acute lymphoblastic leukemia patients. Hematology. 2015;20(9):523–9. 90. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004 Mar 5;303(5663):1532–5. 91. Oliveira E, Bacelar TS, Ciudad J, Ribeiro MCM, Garcia DRN, Sedek L, et al. Altered neutrophil immunophenotypes in childhood B-cell precursor acute lymphoblastic leukemia. Oncotarget. 2016 Apr 4;7(17):24664. 92. Buitenhuis M, Van Deutekom HWM, Verhagen LP, Castor A, Jacobsen SEW, Lammers JWJ, et al. Differential regulation of granulopoiesis by the basic helix-loop-helix transcriptional inhibitors Id1 and Id2. Blood. 2005 Jun 1;105(11):4272–81. 93. Ostafin M, Ciepiela O, Pruchniak M, Wachowska M, Ulińska E, Mrówka P, et al. Dynamic Changes in the Ability to Release Neutrophil ExtraCellular Traps in the Course of Childhood Acute Leukemias. Int J Mol Sci. 2021 Jan 2;22(2):1–11. 94. Liu G jie, Wang Y jie, Yue M, Zhao L mei, Guo YD, Liu Y ping, et al. High expression of TCN1 is a negative prognostic biomarker and can predict neoadjuvant chemosensitivity of colon cancer. Scientific Reports 2020 10:1. 2020 Jul 20;10(1):1–11. 95. Chen J, Cheuk IWY, Siu MT, Yang W, Cheng AS, Shin VY, et al. Human haptoglobin contributes to breast cancer oncogenesis through glycolytic activity modulation. Am J Cancer Res. 2020;10(9):2865. 96. Yang G, Xiong G, Feng M, Zhao F, Qiu J, Liu Y, et al. OLR1 promotes pancreatic cancer metastasis via increased c-Myc expression and transcription of HMGA2. Molecular Cancer Research. 2020 May 1;18(5):685–97. 97. Lussana F, Cavallaro G, De Simone P, Rambaldi A. Optimal Use of Novel Immunotherapeutics in B-Cell Precursor ALL. Cancers (Basel). 2023;15(4):1–23. 98. Zhang H, Rosdahl I. Expression profiles of Id1 and p16 proteins in all-trans-retinoic acid-induced apoptosis and cell cycle re-distribution in melanoma. Cancer Lett. 2005 Jan 10;217(1):33–41. 99. Álvarez-Zúñiga CD, Garza-Veloz I, Martínez-Rendón J, Ureño-Segura M, Delgado-Enciso I, Martinez-Fierro ML. Circulating Biomarkers Associated with the Diagnosis and Prognosis of B-Cell Progenitor Acute Lymphoblastic Leukemia. Cancers (Basel). 2023 Aug 1;15(16):4186. |
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Universidad Nacional de Colombia |
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Bogotá - Medicina - Maestría en Inmunología |
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Facultad de Medicina |
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Bogotá, Colombia |
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Universidad Nacional de Colombia - Sede Bogotá |
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Universidad Nacional de Colombia |
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Atribución-NoComercial 4.0 Internacionalinfo:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Combita Rojas, Alba Lucía6314d25773a6df920534c402dcbbd1b1Orozco Castaño, Carlos Alberto5f6790e238d62c49e2a0516f16a95af6Poveda Garavito, Jenny Nathalya09d2ee2279726b8399cbf11215904bfGrupo de Investigación en Biología del CáncerGrupo de Investigación Traslacional en Oncología0009-0000-6605-873XPoveda Garavito, Jenny Nathaly [0009-0000-6605-873X]Poveda Garavito, Jenny Nathaly [0000074526]https://www.researchgate.net/profile/Jenny-Poveda-Garavito2024-07-18T15:11:19Z2024-07-18T15:11:19Z2024-05-08https://repositorio.unal.edu.co/handle/unal/86560Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/Ilustraciones a color, diagramasEl diagnóstico de leucemia linfoblástica aguda de precursores de células B (BCP-ALL) es una condición que generalmente presenta un pronóstico desfavorable. Investigaciones previas identificaron los genes ID1 e ID3 como predictores de mala respuesta en pacientes adultos colombianos con BCP-ALL, genes que desempeñan un papel crucial en diversos procesos relacionados con el desarrollo del cáncer. En particular, en otros modelos de cáncer, ID1 e ID3 se asociaron con la presencia de poblaciones inmunitarias reguladoras en el microambiente inmunitario tumoral (TIME). Considerando que estudios anteriores han demostrado que el desarrollo de BCP-ALL altera la composición de las células inmunitarias y el microambiente tumoral de la médula ósea (BM), influyendo en la progresión de la enfermedad y la respuesta a la terapia, este estudio tuvo como objetivo analizar la expresión diferencial de ID1 e ID3 y su posible relación con el TIME en pacientes con BCP-ALL. Para llevar a cabo el estudio, se tomaron muestras de BM de seis pacientes con BCP-ALL diagnosticados en el Instituto Nacional de Cancerología de Colombia. Inicialmente, se evaluó la expresión de ID1 e ID3 en células tumorales de BM mediante la técnica de RT-qPCR, dividiendo a los pacientes en dos categorías según la expresión de estos genes (basal y sobreexpresión). Posteriormente, se realizó una caracterización detallada de las poblaciones inmunes presentes en la BM mediante citometría de flujo, abarcando linfocitos T CD4+ (T totales y reguladores), T CD8+, células mieloides supresoras (MDSC), macrófagos (M1 y M2) y natural killer (NK). Además, se llevó a cabo un análisis de RNA-seq para evaluar los genes inmunes asociados con la respuesta contra BCP-ALL, y se analizaron los perfiles TIME utilizando paquetes como DESeq2, CIBERSORT y xCell en RStudio. Además, se consultó la base de datos pública TARGET para corroborar los datos obtenidos. Los resultados revelaron la expresión diferencial de 15,951 genes entre los dos grupos estudiados, con una sobreexpresión destacada de genes asociados con las vías de neutrófilos. El análisis de enriquecimiento de genes mostró una mayor expresión de genes implicados en la degranulación de neutrófilos, la activación de neutrófilos y la inmunidad mediada por neutrófilos. En particular, se observaron diferencias significativas en las poblaciones de neutrófilos, monocitos y linfocitos T CD4+ en pacientes con niveles elevados de ID1 e ID3 en comparación con el grupo con expresión basal. Estos hallazgos fueron consistentes con los datos obtenidos mediante citometría de flujo. En conclusión, los resultados de este estudio sugieren que los niveles de expresión de ID1 e ID3 en células leucémicas (LC) de BCP-ALL están asociados con alteraciones significativas en las poblaciones de TIME, destacando un posible papel inmunomodulador de estos genes, especialmente en las vías de los neutrófilos. Estos hallazgos podrían tener implicaciones importantes para comprender la progresión de la enfermedad y mejorar las estrategias terapéuticas en pacientes con BCP-ALL. (Texto tomado de la fuente)The diagnosis of acute lymphoblastic leukemia of B-cell precursors (BCP-ALL) is a condition that typically carries an unfavorable prognosis. Previous research has identified the genes ID1 and ID3 as predictors of poor response in adult Colombian patients with BCP-ALL. These genes play a crucial role in various processes related to cancer development. Specifically, in other cancer models, ID1 and ID3 have been associated with the presence of regulatory immune populations in the tumor immune microenvironment (TIME). Given that previous studies have demonstrated that the development of BCP-ALL alters the composition of immune cells and the tumor microenvironment in the bone marrow (BM), influencing disease progression and therapy response, this study aimed to analyze the differential expression of ID1 and ID3 and their potential relationship with TIME in BCPALL patients. To conduct the study, BM samples were taken from six patients diagnosed with BCP-ALL at the National Cancer Institute of Colombia. Initially, the expression of ID1 and ID3 in BM tumor cells was evaluated using the RT-qPCR technique, categorizing patients into two groups based on the expression of these genes (basal and overexpression). Subsequently, a detailed characterization of immune cell populations present in BM was performed using flow cytometry, including CD4+ T lymphocytes (total and regulatory), CD8+ T cells, myeloid-derived suppressor cells (MDSC), macrophages (M1 and M2), and natural killer (NK) cells. Additionally, an RNA-seq analysis was conducted to assess immune genes associated with the response against BCP-ALL, and TIME profiles were analyzed using packages such as DESeq2, CIBERSORT, and xCell in RStudio. Furthermore, the public TARGET database was consulted to corroborate the obtained data. The results revealed differential expression of 15,951 genes between the two studied groups, with prominent overexpression of genes associated with neutrophil pathways. Gene enrichment analysis showed increased expression of genes involved in neutrophil degranulation, neutrophil activation, and neutrophil-mediated immunity. Specifically, significant differences were observed in the populations of neutrophils, monocytes, and CD4+ T lymphocytes in patients with elevated levels of ID1 and ID3 compared to the group with basal expression. These findings were consistent with data obtained through flow cytometry. In conclusion, the results of this study suggest that the expression levels of ID1 and ID3 in leukemia cells (LC) of BCP-ALL are associated with significant alterations in TIME populations, highlighting a potential immunomodulatory role of these genes, especially in neutrophil pathways. These findings could have important implications for understanding disease progression and improving therapeutic strategies in BCP-ALL patients.MaestríaMagister en InmunologíaÁspectos Inmunológicos del Cáncerxvi, 83 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Medicina - Maestría en InmunologíaFacultad de MedicinaBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y saludSistema InmunológicoMédula óseaMonitorización InmunológicaImmune SystemBone MarrowMonitoring, ImmunologicLeucemia linfoblásticaLymphoblastic leukemiaLeucemia linfoblástica aguda de células B precursorasSistema inmunitarioMédula óseaMicroambienteInmunovigilanciaID1ID3Relación entre la expresión de ID1 e ID3 y el microambiente tumoral inmune de la médula ósea en adultos con leucemia linfoblástica aguda de células precursoras BRelationship between ID1 and ID3 expression and the bone marrow immune tumor microenvironment in adults with B precursor cell acute lymphoblastic leukemiaTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TM1. Richard-Carpentier G, Kantarjian H, Jabbour E. Recent Advances in Adult Acute Lymphoblastic Leukemia. Curr Hematol Malig Rep. 20192. Roberts KG, Mullighan CG. The Biology of B-Progenitor Acute Lymphoblastic Leukemia. Cold Spring Harb Perspect Med [Internet]. 2020 Jul 1 [cited 2023 Jan 1];10(7):1–22. Available from: https://pubmed.ncbi.nlm.nih.gov/31653664/3. Felipe Combariza J, Casas CP, Rodriguez M. Rev Colomb CanCeRol 2007;11(2):92-100 93.4. Chiarini F, Lonetti A, Evangelisti C, Buontempo F, Orsini E, Evangelisti C, et al. Advances in understanding the acute lymphoblastic leukemia bone marrow microenvironment: From biology to therapeutic targeting. Biochim Biophys Acta Mol Cell Res [Internet]. 2016;1863(3):449–63. Available from: http://dx.doi.org/10.1016/j.bbamcr.2015.08.0155. Cruz-Rodriguez N, Combita AL, Enciso LJ, Raney LF, Pinzon PL, Lozano OC, et al. Prognostic stratification improvement by integrating ID1/ID3/IGJ gene expression signature and immunophenotypic profile in adult patients with B-ALL. Journal of Experimental and Clinical Cancer Research. 2017;36(1):1–12.6. Roschger C, Cabrele C. The Id-protein family in developmental and cancer-associated pathways Fritz Aberger. Cell Communication and Signaling. 2017;15(1):1–26.7. Wang LH, Baker NE. E-proteins and ID-proteins: Helix-loop-helix partners in development and disease. Dev Cell [Internet]. 2015 Nov 11 [cited 2023 Dec 12];35(3):269. Available from: /pmc/articles/PMC4684411/8. Perk J, Iavarone A, Benezra R. Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer. 2005;5(8):603–14.9. Roberts EC, Deed RW, Inoue T, Norton JD, Sharrocks AD. Id Helix-Loop-Helix Proteins Antagonize Pax Transcription Factor Activity by Inhibiting DNA Binding. Mol Cell Biol. 2001 Jan 15;21(2):524–33.10. Ruzinova MB, Benezra R. Id proteins in development , cell cycle and cancer. 2003;13(8):410–8.11. Ling MT, Wang X, Zhang X, Wong YC. The multiple roles of Id-1 in cancer progression. Differentiation. 2006;74(9–10):481–7.12. Nakatsukasa H, Zhang D, Maruyama T, Chen H, Cui K, Ishikawa M, et al. The DNA-binding inhibitor Id3 regulates IL-9 production in CD4 + T cells. Nat Immunol. 2015;16(10):1077–84.13. Melief J, Pico de Coaña Y, Maas R, Fennemann FL, Wolodarski M, Hansson J, et al. High expression of ID1 in monocytes is strongly associated with phenotypic and functional MDSC markers in advanced melanoma. Cancer Immunology, Immunotherapy. 2020;69(4):513–22.14. Ma C, Witkowski MT, Harris J, Dolgalev I, Sreeram S, Qian W, et al. Leukemia-on-a-chip: Dissecting the chemoresistance mechanisms in B cell acute lymphoblastic leukemia bone marrow niche. Sci Adv. 2020 Oct 28;6(44).15. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394–424.16. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019 Apr 15;144(8):1941–53.17. Hoelzer D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C. Acute lymphoblastic leukaemia in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2016;27:v69–82.18. Schwab C, Harrison CJ. Advances in B-cell Precursor Acute Lymphoblastic Leukemia Genomics. Hemasphere. 2018;1.19. Paul S, Kantarjian H, Jabbour EJ. Adult Acute Lymphoblastic Leukemia. Vol. 91, Mayo Clinic Proceedings. Elsevier Ltd; 2016. p. 1645–66.20. Papaspyridonos M, Matei I, Huang Y, Andre R, Brazier-mitouart H, Waite JC, et al. Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation. 2015;21. Gloury R, Zotos D, Zuidscherwoude M, Masson F, Liao Y, Hasbold J, et al. Dynamic changes in Id3 and E-protein activity orchestrate germinal center and plasma cell development. Journal of Experimental Medicine. 2016;213(6):1095–111.22. Lasorella A, Benezra R, Iavarone A. The ID proteins: Master regulators of cancer stem cells and tumour aggressiveness. Nat Rev Cancer. 2014;14(2):77–91.23. Stankovic T, Marston E. MOLECULAR MECHANISMS INVOLVED IN CHEMORESISTANCE IN PAEDIATRIC ACUTE LYMPHOBLASTIC LEUKAEMIA. 2008;136:187–92.24. Passaro D, Quang CT, Ghysdael J. Microenvironmental cues for T-cell acute lymphoblastic leukemia development. Immunol Rev. 2016;271(1):156–72.25. Höpken UE, Rehm A. Targeting the Tumor Microenvironment of Leukemia and Lymphoma. Trends Cancer. 2019;5(6):351–64.26. Houshmand M, Blanco TM, Circosta P, Yazdi N, Kazemi A, Saglio G, et al. Bone marrow microenvironment: The guardian of leukemia stem cells. Vol. 11, World Journal of Stem Cells. Baishideng Publishing Group Co; 2019. p. 476–90.27. Rabe JL, Gardner L, Hunter R, Fonseca JA, Dougan J, Gearheart CM, et al. IL12 abrogates calcineurin-dependent immune evasion during leukemia progression. Cancer Res. 2019;79(14):3702–13.28. Hunter R, Imbach KJ, Zhou C, Dougan J, Hamilton JAG, Chen KZ, et al. B-cell acute lymphoblastic leukemia promotes an immune suppressive microenvironment that can be overcome by IL-12. Scientific Reports 2022 12:1. 2022 Jul 13;12(1):1–13.29. Malard F, Mohty M. Seminar Acute lymphoblastic leukaemia. The Lancet. 2020;395(10230):1146–62.30. Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. The Lancet. 2013;381(9881):1943–55.31. Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505(7483):327–34.32. Hagman J. Transcriptional Regulation of Early B Cell Development. Second Edi. Molecular Biology of B Cells: Second Edition. Elsevier Ltd; 2015. 35–53 p.33. Engel I, Murre C. The function of E- and ID proteins in lymphocyte development. Nat Rev Immunol. 2001;1(3):193–9.34. Loghavi S, Kutok JL, Jorgensen JL. B-acute lymphoblastic leukemia/lymphoblastic lymphoma. Am J Clin Pathol. 2015;144(3):393–410.35. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017;7(6):e577.36. Cobaleda C, Sánchez-García I. B-cell acute lymphoblastic leukaemia: Towards understanding its cellular origin. BioEssays. 2009;31(6):600–9.37. Iacobucci I, Mullighan CG. Genetic basis of acute lymphoblastic leukemia. Journal of Clinical Oncology. 2017;35(9):975–83.38. Faderl S, O’Brien S, Pui CH, Stock W, Wetzler M, Hoelzer D, et al. Adult acute lymphoblastic leukemia: Concepts and strategies. Cancer. 2010;116(5):1165–76.39. Sas V, Moisoiu V, Teodorescu P, Tranca S, Pop L, Iluta S, et al. Approach to the Adult Acute Lymphoblastic Leukemia Patient. J Clin Med. 2019;8(8):1175.40. Bassan R, Bourquin JP, DeAngelo DJ, Chiaretti S. New approaches to the management of adult acute lymphoblastic leukemia. Journal of Clinical Oncology. 2018;36(35):3504–19.41. Muffly LS, Reizine N, Stock W. Management of acute lymphoblastic leukemia in young adults. Clinical Advances in Hematology and Oncology. 2018;16(2):138–46.42. Narayanan S, Shami PJ. Treatment of acute lymphoblastic leukemia in adults. Crit Rev Oncol Hematol. 2012;81(1):94–102.43. Malouf C, Ottersbach K. Molecular processes involved in B cell acute lymphoblastic leukaemia. Cellular and Molecular Life Sciences. 2018;75(3):417–46.44. Rafei H, Kantarjian HM, Jabbour EJ. Recent advances in the treatment of acute lymphoblastic leukemia. Leuk Lymphoma. 2019;60(11):2606–21.45. Hoelzer D, Bassan R, Boissel N, Roddie C, Ribera JM, Jerkeman M. ESMO Clinical Practice Guideline interim update on the use of targeted therapy in acute lymphoblastic leukaemia. Annals of Oncology [Internet]. 2023 Oct [cited 2023 Dec 4];0(0). Available from: http://www.annalsofoncology.org/article/S0923753423040097/fulltext46. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. New England Journal of Medicine. 2017 Mar 2;376(9):836–47.47. Cruz-Rodriguez N, Combita AL, Enciso LJ, Quijano SM, Pinzon PL, Lozano OC, et al. High expression of ID family and IGJ genes signature as predictor of low induction treatment response and worst survival in adult Hispanic patients with B-Acute lymphoblastic leukemia. Journal of Experimental and Clinical Cancer Research. 2016;35(1):1–14.48. Mami N Ben, Mohty M, Chambost H, Gaugler B, Olive D. Blood dendritic cells in patients with acute lymphoblastic leukaemia. Br J Haematol. 2004 Jul;126(1):77–80.49. Liu C, Wang HC, Yu S, Jin R, Tang H, Liu YF, et al. Id1 Expression Promotes T Regulatory Cell Differentiation by Facilitating TCR Costimulation. The Journal of Immunology. 2014;193(2):663–72.50. Yuen HF, Chan YP, Chan KK, Chu YY, Wong MLY, Law SYK, et al. Id-1 and Id-2 are markers for metastasis and prognosis in oesophageal squamous cell carcinoma. Br J Cancer. 2007;97(10):1409–15.51. Nair R, Teo WS, Mittal V, Swarbrick A. ID Proteins Regulate Diverse Aspects of Cancer Progression and Provide Novel Therapeutic Opportunities. 2014;22(8):1407–15.52. Weiler S, Ademokun JA, Norton JD. ID helix-loop-helix proteins as determinants of cell survival in B-cell chronic lymphocytic leukemia cells in vitro. 2015;1–20.53. Zebedee Z, Hara E. Id proteins in cell cycle control and cellular senescence. Oncogene. 2001;20(58 REV. ISS. 8):8317–25.54. Mellman I, Chen DS, Powles T, Turley SJ. The cancer-immunity cycle: Indication, genotype, and immunotype. Immunity. 2023 Oct 10;56(10):2188–205.55. Roy S, Zhuang Y. Paradoxical role of Id proteins in regulating tumorigenic potential of lymphoid cells. Vol. 12, Frontiers of Medicine. Higher Education Press; 2018. p. 374–86.56. Witkowski MT, Dolgalev I, Evensen NA, Tsirigos A, Carroll WL. Article Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia. Cancer Cell. 2020;37(6):867-882.e12.57. Anderson D, Skut P, Hughes AM, Ferrari E, Tickner J, Xu J, et al. The bone marrow microenvironment of pre B acute lymphoblastic leukemia at single cell resolution. Sci Rep. 2020;1–14.58. Méndez-Ferrer S, Bonnet D, Steensma DP, Hasserjian RP, Ghobrial IM, Gribben JG, et al. Bone marrow niches in haematological malignancies. Nat Rev Cancer. 2020;59. Forte D, Krause DS, Andreeff M, Bonnet D, Méndez-Ferrer S. Updates on the hematologic tumor microenvironment and its therapeutic targeting. Haematologica. 2019;104(10):1928–34.60. Man Y, Yao X, Yang T, Wang Y. Hematopoietic Stem Cell Niche During Homeostasis, Malignancy, and Bone Marrow Transplantation. Front Cell Dev Biol. 2021;9(January):1–11.61. Meyer LK, Hermiston ML. The bone marrow microenvironment as a mediator of chemoresistance in acute lymphoblastic leukemia. 2019;1–14.62. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93–106.63. Reagan MR, Rosen CJ. Navigating the bone marrow niche: Translational insights and cancer-driven dysfunction. Nat Rev Rheumatol. 2016;12(3):154–68.64. Zhao E, Xu H, Wang L, Kryczek I, Wu K, Hu Y, et al. Bone marrow and the control of immunity. 2012;(July 2011):11–9.65. Mercier FE, Ragu C, Scadden DT. The bone marrow at the crossroads of blood and immunity. Nat Rev Immunol. 2012;12(1):49–60.66. Riether C, Schürch CM, Ochsenbein AF. Regulation of hematopoietic and leukemic stem cells by the immune system. Cell Death Differ. 2015;22(2):187–98.67. Autio M, Leivonen S katri, Brück O, Mustjoki S. Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma. 2021;106(3).68. Fujisaki J, Wu J, Carlson AL, Silberstein L, Putheti P, Larocca R, et al. In vivo imaging of T reg cells providing immune privilege to the haematopoietic stem-cell niche. Nature. 2011;474(7350):216–20.69. Shang S, Yang C, Chen F, Xiang R shen, Zhang H, Dai S yuan, et al. ID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer. Nat Commun. 2023;14(1).70. Prabhu S, Ignatova A, Park ST, Sun XH. Regulation of the expression of cyclin-dependent kinase inhibitor p21 by E2A and Id proteins. Mol Cell Biol. 1997 Oct 1;17(10):5888.71. Pan L, Sato S, Frederick JP, Sun XH, Zhuang Y. Impaired Immune Responses and B-Cell Proliferation in Mice Lacking the Id3 Gene. Mol Cell Biol. 1999;19(9):5969–80.72. Zhao Q, Wang Y, Yu D, Leng JY, Zhao Y, Chu M, et al. Comprehensive analysis of ID genes reveals the clinical and prognostic value of ID3 expression in acute myeloid leukemia using bioinformatics identification and experimental validation. BMC Cancer. 2022;22(1):1–12.74. Castañon E, Bosch-Barrera J, López I, Collado V, Moreno M, López-Picazo JM, et al. Id1 and Id3 co-expression correlates with clinical outcome in stage III-N2 non-small cell lung cancer patients treated with definitive chemoradiotherapy. J Transl Med. 2013 Jan 11;11(1):1–8.75. O’Brien CA, Kreso A, Ryan P, Hermans KG, Gibson L, Wang Y, et al. ID1 and ID3 Regulate the Self-Renewal Capacity of Human Colon Cancer-Initiating Cells through p21. Cancer Cell. 2012 Jun 12;21(6):777–92.76. Liu Y feng, Chen Y ying, He Y yi, Wang J yi, Yang J ping, Zhong S ling, et al. Expansion and activation of granulocytic, myeloid-derived suppressor cells in childhood precursor B cell acute lymphoblastic leukemia. J Leukoc Biol. 2017;102(2):449–58.77. Song JX, Wen Y, Li RW, Dong T, Tang YF, Zhang JJ, et al. Phenotypic characterization of macrophages in the BMB sample of human acute leukemia. Ann Hematol. 2020;99(3):539–47.78. Zhang Z, Liu S, Zhang B, Qiao L, Zhang Y, Zhang Y. T Cell Dysfunction and Exhaustion in Cancer. 2020;8(February).79. Jin Y, Hu P, Sun H, Yang C, Zhai J, Wang Y, et al. Expression of Id3 represses exhaustion of anti-tumor CD8 T cells in liver cancer. Mol Immunol. 2022 Apr 1;144:117–26.80. Lipp JJ, Wang L, Yang H, Yao F, Harrer N, Müller S, et al. Functional and molecular characterization of PD1+ tumor-infiltrating lymphocytes from lung cancer patients. Oncoimmunology. 2022 Dec 31;11(1).81. Rauch KS, Hils M, Lupar E, Minguet S, Sigvardsson M, Rottenberg ME, et al. Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a Transcriptional Network of E47, Spi-B, and SOCS3. Cell Rep. 2016;17(11):2827–36.82. Xue G, Zheng N, Fang J, Jin G, Li X, Dotti G, et al. Adoptive cell therapy with tumor-specific Th9 cells induces viral mimicry to eliminate antigen-loss-variant tumor cells. Cancer Cell. 2021 Dec 13;39(12):1610-1622.e9.83. Lustfeld I, Ahlmann M. High Proportions of CD4 + T Cells among Residual Bone Marrow T Cells in Childhood Acute Lymphoblastic Leukemia Are Associated with Favorable Early Responses. 2014;28–36.84. Salem ML, El-Shanshory MR, Abdou SH, Attia MS, Sobhy SM, Zidan MF, et al. Chemotherapy alters the increased numbers of myeloid-derived suppressor and regulatory T cells in children with acute lymphoblastic leukemia. Immunopharmacol Immunotoxicol. 2018;40(2):158–67.85. El-maadawy EA, Elshal MF, Bakry RM, Moussa MM, El-Naby SH, Talaat RM. Regulation of CD4+CD25+FOXP3+ cells in Pediatric Acute Lymphoblastic Leukemia (ALL): Implication of cytokines and miRNAs. Mol Immunol. 2020;124(March):1–8.86. Niedźwiecki M, Budziło O, Zieliński M, Adamkiewicz-Drożyńska E, Maciejka-Kembłowska L, Szczepański T, et al. CD4+CD25highCD127low/−FoxP3+ Regulatory T Cell Subpopulations in the Bone Marrow and Peripheral Blood of Children with ALL: Brief Report. J Immunol Res. 2018;2018.87. Wu CP, Qing X, Wu CY, Zhu H, Zhou HY. Immunophenotype and increased presence of CD4 +CD25 + regulatory T cells in patients with acute lymphoblastic leukemia. Oncol Lett. 2012;3(2):421–4.88. Liu SX, Xiao HR, Wang GB, Chen XW, Li CG, Mai HR, et al. Preliminary investigation on the abnormal mechanism of cd4+foxp3+cd25high regulatory t cells in pediatric b-cell acute lymphoblastic leukemia. Exp Ther Med. 2018;16(2):1433–41.89. Idris SZ, Hassan N, Lee LJ, Md Noor S, Osman R, Abdul-Jalil M, et al. Increased regulatory T cells in acute lymphoblastic leukemia patients. Hematology. 2015;20(9):523–9.90. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004 Mar 5;303(5663):1532–5.91. Oliveira E, Bacelar TS, Ciudad J, Ribeiro MCM, Garcia DRN, Sedek L, et al. Altered neutrophil immunophenotypes in childhood B-cell precursor acute lymphoblastic leukemia. Oncotarget. 2016 Apr 4;7(17):24664.92. Buitenhuis M, Van Deutekom HWM, Verhagen LP, Castor A, Jacobsen SEW, Lammers JWJ, et al. Differential regulation of granulopoiesis by the basic helix-loop-helix transcriptional inhibitors Id1 and Id2. Blood. 2005 Jun 1;105(11):4272–81.93. Ostafin M, Ciepiela O, Pruchniak M, Wachowska M, Ulińska E, Mrówka P, et al. Dynamic Changes in the Ability to Release Neutrophil ExtraCellular Traps in the Course of Childhood Acute Leukemias. Int J Mol Sci. 2021 Jan 2;22(2):1–11.94. Liu G jie, Wang Y jie, Yue M, Zhao L mei, Guo YD, Liu Y ping, et al. High expression of TCN1 is a negative prognostic biomarker and can predict neoadjuvant chemosensitivity of colon cancer. Scientific Reports 2020 10:1. 2020 Jul 20;10(1):1–11.95. Chen J, Cheuk IWY, Siu MT, Yang W, Cheng AS, Shin VY, et al. Human haptoglobin contributes to breast cancer oncogenesis through glycolytic activity modulation. Am J Cancer Res. 2020;10(9):2865.96. Yang G, Xiong G, Feng M, Zhao F, Qiu J, Liu Y, et al. OLR1 promotes pancreatic cancer metastasis via increased c-Myc expression and transcription of HMGA2. Molecular Cancer Research. 2020 May 1;18(5):685–97.97. Lussana F, Cavallaro G, De Simone P, Rambaldi A. Optimal Use of Novel Immunotherapeutics in B-Cell Precursor ALL. Cancers (Basel). 2023;15(4):1–23.98. Zhang H, Rosdahl I. Expression profiles of Id1 and p16 proteins in all-trans-retinoic acid-induced apoptosis and cell cycle re-distribution in melanoma. Cancer Lett. 2005 Jan 10;217(1):33–41.99. Álvarez-Zúñiga CD, Garza-Veloz I, Martínez-Rendón J, Ureño-Segura M, Delgado-Enciso I, Martinez-Fierro ML. Circulating Biomarkers Associated with the Diagnosis and Prognosis of B-Cell Progenitor Acute Lymphoblastic Leukemia. Cancers (Basel). 2023 Aug 1;15(16):4186.Instituto Nacional de CancerologíaBibliotecariosEstudiantesInvestigadoresMaestrosMedios de comunicaciónPúblico generalLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/86560/3/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD53ORIGINAL1012387881.2024.pdf1012387881.2024.pdfTesis de Magister en Inmunologíaapplication/pdf3472839https://repositorio.unal.edu.co/bitstream/unal/86560/4/1012387881.2024.pdfe067efc2612168ee34265728b83e6b87MD54THUMBNAIL1012387881.2024.pdf.jpg1012387881.2024.pdf.jpgGenerated Thumbnailimage/jpeg5585https://repositorio.unal.edu.co/bitstream/unal/86560/5/1012387881.2024.pdf.jpg213f2f0cdf2f5d8f90339e513898a1cdMD55unal/86560oai:repositorio.unal.edu.co:unal/865602024-08-25 23:10:52.837Repositorio Institucional Universidad Nacional de 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