Skip to main content

Advertisement

SpringerLink
Log in

The pleiotropic roles of EZH2 in T-cell immunity and immunotherapy

  • Progress in Hematology
  • Epigenetics in lymphocyte and lymphoma: EZH2 as an easy-to-access therapeutic target?
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

EZH2 is a histone methyltransferase. It catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3) to control gene transcription critical for cell proliferation, differentiation, expansion, and function. For instance, EZH2 plays a central role in regulating T-cell immune responses. EZH2 restrains terminal differentiation of effector CD8 T cells, promotes formation of precursor and mature memory CD8 T cells, regulates appropriate lineage-specification and identity maintenance of helper CD4 T cells, and maintains survival of differentiated antigen-specific T cells. Most importantly, EZH2 is shown to be important for reinvigoration of exhausted chimeric antigen receptor (CAR) T cells. Dysregulated EZH2 function has been linked to many forms of cancer, including lymphomas and solid tumors. In B-cell lymphoid malignancies, EZH2 is overexpressed to drive tumorigenesis. These specific effects of EZH2, in the context of its roles in catalyzing H3K27me3 and orchestrating gene transcription programs in both normal and malignant cells, establishes EZH2 as a unique target for drug development. Here, we will discuss Ezh2 regulation of T-cell immunity, EZH2-mediated lymphomagenesis, and therapeutic benefits of EZH2 inhibitors to the treatment of lymphoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig.1
Fig.2

Similar content being viewed by others

References

  1. Cao R, Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev. 2004;14:155–64.

    Article  CAS  PubMed  Google Scholar 

  2. Cao R, et al. Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science. 2002;298:1039–43.

    Article  CAS  PubMed  Google Scholar 

  3. Vire E, et al. The polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439:871–4.

    Article  CAS  PubMed  Google Scholar 

  4. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 2002;16:2893–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Czermin B, et al. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell. 2002;111:185–96.

    Article  CAS  PubMed  Google Scholar 

  6. Ciferri C, et al. Molecular architecture of human polycomb repressive complex 2. Elife. 2012;1: e00005.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Margueron R, Reinberg D. The polycomb complex PRC2 and its mark in life. Nature. 2011;469:343–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 2004;23:4061–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Simon JA, Kingston RE. Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol. 2009;10:697–708.

    Article  CAS  PubMed  Google Scholar 

  10. Ezhkova E, et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell. 2009;136:1122–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gonzalez ME, et al. EZH2 expands breast stem cells through activation of NOTCH1 signaling. Proc Natl Acad Sci U S A. 2014;111:3098–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Velichutina I, et al. EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood. 2010;116:5247–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kato K, et al. Identification of stem cell transcriptional programs normally expressed in embryonic and neural stem cells in alloreactive CD8+ T cells mediating graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16:751–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. O’Carroll D, et al. The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol. 2001;21:4330–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kamminga LM, et al. The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood. 2006;107:2170–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. He S, et al. The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease. Blood. 2013;122:4119–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tong Q, et al. Ezh2 regulates transcriptional and posttranslational expression of t-bet and promotes Th1 cell responses mediating aplastic anemia in mice. J Immunol. 2014;192:5012–22.

    Article  CAS  PubMed  Google Scholar 

  18. He S, et al. Ezh2 phosphorylation state determines its capacity to maintain CD8(+) T memory precursors for antitumor immunity. Nat Commun. 2017;8:2125.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Tumes DJ, et al. The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity. 2013;39:819–32.

    Article  CAS  PubMed  Google Scholar 

  20. Gray SM, Amezquita RA, Guan T, Kleinstein SH, Kaech SM. Polycomb repressive complex 2-mediated chromatin repression guides effector CD8(+) T cell terminal differentiation and loss of multipotency. Immunity. 2017;46:596–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kakaradov B, et al. Early transcriptional and epigenetic regulation of CD8(+) T cell differentiation revealed by single-cell RNA sequencing. Nat Immunol. 2017;18:422–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lu C, et al. Regulation of tumor angiogenesis by EZH2. Cancer Cell. 2010;18:185–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Varambally S, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624–9.

    Article  CAS  PubMed  Google Scholar 

  24. Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22:128–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chammas P, Mocavini I, Di Croce L. Engaging chromatin: PRC2 structure meets function. Br J Cancer. 2020;122:315–28.

    Article  CAS  PubMed  Google Scholar 

  26. Morin RD, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42:181–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006;6:846–56.

    Article  CAS  PubMed  Google Scholar 

  28. Comet I, Riising EM, Leblanc B, Helin K. Maintaining cell identity: PRC2-mediated regulation of transcription and cancer. Nat Rev Cancer. 2016;16:803–10.

    Article  CAS  PubMed  Google Scholar 

  29. Bates SE. Epigenetic therapies for cancer. N Engl J Med. 2020;383:650–63.

    Article  CAS  PubMed  Google Scholar 

  30. Sneeringer CJ, et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci U S A. 2010;107:20980–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wigle TJ, et al. The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states. FEBS Lett. 2011;585:3011–4.

    Article  CAS  PubMed  Google Scholar 

  32. Yap DB, et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2011;117:2451–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Simon C, et al. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev. 2012;26:651–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bodor C, et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood. 2013;122:3165–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yan J, et al. EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity. Blood. 2013;121:4512–20.

    Article  CAS  PubMed  Google Scholar 

  36. Ntziachristos P, et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med. 2012;18:298–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang J, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481:157–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ntziachristos P, et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature. 2014;514:513–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol. 2012;12:443–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat Med. 2005;11:1299–305.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG. Alloreactive Memory T Cells Are responsible for the persistence of graft-versus-host disease. J Immunol. 2005;174:3051–8.

    Article  CAS  PubMed  Google Scholar 

  42. He S, et al. Inhibition of histone methylation arrests ongoing graft-versus-host disease in mice by selectively inducing apoptosis of alloreactive effector T cells. Blood. 2012;119:1274–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010;28:445–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Amsen D, Antov A, Flavell RA. The different faces of notch in T-helper-cell differentiation. Nat Rev Immunol. 2009;9:116–24.

    Article  CAS  PubMed  Google Scholar 

  45. Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity. 2009;30:646–55.

    Article  CAS  PubMed  Google Scholar 

  46. Wilson CB, Rowell E, Sekimata M. Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol. 2009;9:91–105.

    Article  CAS  PubMed  Google Scholar 

  47. Pereira JD, et al. Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc Natl Acad Sci U S A. 2010;107:15957–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wei G, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 2009;30:155–67.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Bernstein BE, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315–26.

    Article  CAS  PubMed  Google Scholar 

  50. Li F, et al. Ezh2 programs TFH differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf. Nat Commun. 2018;9:5452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29:621–63.

    Article  CAS  PubMed  Google Scholar 

  52. Choi YS, et al. Bcl6 expressing follicular helper CD4 T cells are fate committed early and have the capacity to form memory. J Immunol. 2013;190:4014–26.

    Article  CAS  PubMed  Google Scholar 

  53. He C, et al. EZH2 promotes T follicular helper cell differentiation through enhancing STAT3 phosphorylation in patients with primary sjogren’s syndrome. Front Immunol. 2022;13: 922871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bettelli E, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8.

    Article  CAS  PubMed  Google Scholar 

  55. Yang XP, et al. EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion. Sci Rep. 2015;5:10643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhang Y, et al. The polycomb repressive complex 2 governs life and death of peripheral T cells. Blood. 2014;124:737–49.

    Article  CAS  PubMed  Google Scholar 

  57. DuPage M, et al. The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation. Immunity. 2015;42:227–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jensen MC, Riddell SR. Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev. 2014;257:127–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012;12:269–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol. 2012;12:749–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Paley MA, et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science. 2012;338:1220–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fearon DT. The expansion and maintenance of antigen-selected CD8(+) T cell clones. Adv Immunol. 2007;96:103–39.

    Article  CAS  PubMed  Google Scholar 

  63. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Barber DL, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–7.

    Article  CAS  PubMed  Google Scholar 

  65. Frebel H, et al. Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice. J Exp Med. 2012;209:2485–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Khan O, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature. 2019;571:211–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chen J, et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature. 2019;567:530–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jadhav RR, et al. Epigenetic signature of PD-1+ TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade. Proc Natl Acad Sci U S A. 2019;116:14113–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Weber EW, et al. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science. 2021;372:6537.

    Article  Google Scholar 

  70. Honma D, et al. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 2017;108:2069–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. 2012;30:429–57.

    Article  CAS  PubMed  Google Scholar 

  72. Su IH, et al. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol. 2003;4:124–31.

    Article  CAS  PubMed  Google Scholar 

  73. Beguelin W, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013;23:677–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Caganova M, et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Investig. 2013;123:5009–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. McCabe MT, et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A. 2012;109:2989–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Morin RD, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476:298–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. McCabe MT, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108–12.

    Article  CAS  PubMed  Google Scholar 

  78. Ennishi D, et al. Molecular and genetic characterization of MHC deficiency identifies EZH2 as therapeutic target for enhancing immune recognition. Cancer Discov. 2019;9:546–63.

    Article  PubMed  Google Scholar 

  79. Yuan H, et al. The EZH2 inhibitor tazemetostat upregulates the expression of CCL17/TARC in B-cell lymphoma and enhances T-cell recruitment. Cancer Sci. 2021;112:4604–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Peng D, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 2015;527:249–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhao E, et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol. 2015;17:95.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Zhou L, Mudianto T, Ma X, Riley R, Uppaluri R. Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti-PD-1 Resistance in Head and Neck Cancer. Clin Cancer Res. 2020;26:290–300.

    Article  CAS  PubMed  Google Scholar 

  83. Zingg D, et al. The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep. 2017;20:854–67.

    Article  CAS  PubMed  Google Scholar 

  84. Goswami S, et al. Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J Clin Invest. 2018;128:3813–8.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Bantignies F, Cavalli G. Cellular memory and dynamic regulation of polycomb group proteins. Curr Opin Cell Biol. 2006;18:275–83.

    Article  CAS  PubMed  Google Scholar 

  86. Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 1999;397:164–8.

    Article  CAS  PubMed  Google Scholar 

  87. Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G. Genome regulation by polycomb and trithorax proteins. Cell. 2007;128:735–45.

    Article  CAS  PubMed  Google Scholar 

  88. Knutson SK, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012;8:890–6.

    Article  CAS  PubMed  Google Scholar 

  89. Yamagishi M, et al. Targeting Excessive EZH1 and EZH2 activities for abnormal histone methylation and transcription network in malignant lymphomas. Cell Rep. 2019;29:2321-2337 e7.

    Article  CAS  PubMed  Google Scholar 

  90. Gulati N, Beguelin W, Giulino-Roth L. Enhancer of zeste homolog 2 (EZH2) inhibitors. Leuk Lymphoma. 2018;59:1574–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kung PP, et al. Optimization of orally bioavailable enhancer of zeste homolog 2 (EZH2) inhibitors using ligand and property-based design strategies: identification of development candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2- dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497). J Med Chem. 2018;61:650–65.

    Article  CAS  PubMed  Google Scholar 

  92. Straining R, Eighmy W. Tazemetostat: EZH2 Inhibitor. J Adv Pract Oncol. 2022;13:158–63.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Morschhauser F, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21:1433–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Italiano A, et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 2018;19:649–59.

    Article  CAS  PubMed  Google Scholar 

  95. Knutson SK, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014;13:842–54.

    Article  CAS  PubMed  Google Scholar 

  96. Knutson SK, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013;110:7922–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Izutsu K, et al. Phase II study of tazemetostat for relapsed or refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan. Cancer Sci. 2021;112:3627–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ji MM, et al. Histone modifier gene mutations in peripheral T-cell lymphoma not otherwise specified. Haematologica. 2018;103:679–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Huang Y, et al. Discovery of the clinical candidate MAK683: an EED-directed, allosteric, and selective PRC2 inhibitor for the treatment of advanced malignancies. J Med Chem. 2022;65:5317–33.

    Article  CAS  PubMed  Google Scholar 

  100. Montgomery ND, et al. The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Curr Biol. 2005;15:942–7.

    Article  CAS  PubMed  Google Scholar 

  101. Huang Y, et al. Discovery of first-in-class, potent, and orally bioavailable embryonic ectoderm development (EED) inhibitor with robust anticancer efficacy. J Med Chem. 2017;60:2215–26.

    Article  CAS  PubMed  Google Scholar 

  102. Bisserier M, Wajapeyee N. Mechanisms of resistance to EZH2 inhibitors in diffuse large B-cell lymphomas. Blood. 2018;131:2125–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Xu K, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338:1465–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kim J, et al. Polycomb- and methylation-independent roles of EZH2 as a transcription activator. Cell Rep. 2018;25:2808-2820 e.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ma A, et al. Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol. 2020;16:214–22.

    Article  CAS  PubMed  Google Scholar 

  106. Huang Q, et al. Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice. Blood. 2017;129:2737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zaiken MC, et al. BET-bromodomain and EZH2 inhibitor treated chronic GVHD mice have blunted germinal centers with distinct transcriptomes. Blood. 2022;139:2983.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

National Institute of Health/National Institute of Allergy and Infectious Diseases.

Author information

Authors and Affiliations

  1. Center for Discovery & Innovation, Hackensack University Medical Center, Nutley, NJ, USA

    Ying Wang, Tien Bui & Yi Zhang

Authors
  1. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tien Bui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi Zhang.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Bui, T. & Zhang, Y. The pleiotropic roles of EZH2 in T-cell immunity and immunotherapy. Int J Hematol 116, 837–845 (2022). https://doi.org/10.1007/s12185-022-03466-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-022-03466-x

Keywords

Search

Navigation