Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Emerging epigenetic-modulating therapies in lymphoma

Abstract

Despite considerable advances in the treatment of lymphoma, the prognosis of patients with relapsed and/or refractory disease continues to be poor; thus, a continued need exists for the development of novel approaches and therapies. Epigenetic dysregulation might drive and/or promote tumorigenesis in various types of malignancies and is prevalent in both B cell and T cell lymphomas. Over the past decade, a large number of epigenetic-modifying agents have been developed and introduced into the clinical management of patients with haematological malignancies. In this Review, we provide a concise overview of the most promising epigenetic therapies for the treatment of lymphomas, including inhibitors of histone deacetylases (HDACs), DNA methyltransferases (DNMTs), enhancer of zeste homologue 2 (EZH2), bromodomain and extra-terminal domain proteins (BETs), protein arginine N-methyltransferases (PRMTs) and isocitrate dehydrogenases (IDHs), and highlight the most promising future directions of research in this area.

Key points

  • Epigenetic-modifying drugs are routinely used in acute myeloid leukaemia, myelodysplastic syndrome and T cell lymphomas, but their role in other malignancies, including B cell lymphomas, has not yet been established.

  • B cell lymphomas typically have a high frequency of somatic mutations in genes encoding enzymes with a role in epigenetic modifications.

  • In addition to expanding the role of histone deacetylase and DNA methyltransferase inhibitors for new indications, novel classes of agents are also being investigated for lymphoma, including enhancer of zeste homologue 2 (EZH2), bromodomain and extra-terminal domain protein (BET), isocitrate dehydrogenase (IDH) and protein arginine N-methyltransferase 5 (PRMT5) inhibitors.

  • The selection and rational prioritization of epigenetic agents are important for both designing future studies and choosing the most appropriate agents for patients in clinical practice.

  • Potential future research directions include investigating novel combinations, exploring the therapeutic role of targeting new epigenetic pathways and discovering new biomarkers to guide patient selection.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Timeline of FDA approvals of epigenetic-modulating therapies for patients with lymphomas.
Fig. 2: Mechanisms of action of common epigenetic enzymes.

References

  1. 1.

    Lunning, M. A. Mutation of chromatin modifiers; an emerging hallmark of germinal center B cell lymphoma. Blood Cancer J. 5, e361 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Morin, R. D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011). This paper demonstrates that somatic mutations in genes encoding histone-modifying enzymes, including KMT2D and MEF2B, are frequent in DLBCL and FL.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B cell lymphomas of germinal-cell origin. Nat. Genet. 42, 181–184 (2010). This paper demonstrates that somatic mutations of EZH2 are frequent in GCB-like DLBCL and FL.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B cell lymphoma. Nat. Genet. 43, 830–836 (2011). This study reveals that the coding genome of DLBCL typically contains more than 30 gene alterations per patient, including a high frequency of KMT2D mutations.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B cell lymphoma. Nature 471, 189–195 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Chambwe, N. et al. Variability in DNA methylation defines novel epigenetic subgroups of DLBCL associated with different clinical outcomes. Blood 123, 1699–1708 (2014). This study demonstrates an association between degree of DNA methylation variability and patient survival outcomes in DLBCL.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    McClure, J. J. et al. Advances and challenges of HDAC inhibitors in cancer therapeutics. Adv. Cancer Res. 138, 183–211 (2018).

    PubMed  Google Scholar 

  8. 8.

    Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Bereshchenko, O. R. et al. Acetylation inactivates the transcriptional repressor BCL6. Nat. Genet. 32, 606–613 (2002).

    CAS  PubMed  Google Scholar 

  10. 10.

    Zhang, J. et al. The CREBBP acetyltransferase is a haploinsufficient tumor suppressor in B cell lymphoma. Cancer Discov. 7, 322–337 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Jiang, Y. et al. CREBBP inactivation promotes the development of HDAC3-dependent lymphomas. Cancer Discov. 7, 38–53 (2017). This paper demonstrates that somatic mutations in CREBBP result in unopposed deacetylation by HDAC3, leading to development of germinal cell-derived lymphomas in mice.

    CAS  PubMed  Google Scholar 

  12. 12.

    Green, M. R. et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc. Natl Acad. Sci. USA 112, 1116–1125 (2015).

    Google Scholar 

  13. 13.

    Gorrini, C. et al. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 448, 1063–1067 (2007).

    CAS  PubMed  Google Scholar 

  14. 14.

    Castro, P. G. et al. The HDAC inhibitor panobinostat (LBH589) exerts in vivo anti-leukaemic activity against MLL-rearranged acute lymphoblastic leukaemia and involves the RNF20/RNF40/WAC-H2B ubiquitination axis. Leukemia 32, 323–331 (2018).

    Google Scholar 

  15. 15.

    Rozati, S. et al. Romidepsin and azacitidine synergize in their epigenetic modulatory effects to induce apoptosis in CTCL. Clin. Cancer Res. 22, 2020–2031 (2016).

    CAS  PubMed  Google Scholar 

  16. 16.

    Ageberg, M. et al. The histone deacetylase inhibitor valproic acid sensitizes diffuse large B cell lymphoma cell lines to CHOP-induced cell death. Am. J. Transl Res. 5, 170–183 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Buglio, D. et al. Vorinostat inhibits STAT6-mediated Th2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines. Blood 112, 1424–1433 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Klein, J. M. et al. The histone deacetylase inhibitor LBH589 (panobinostat) modulates the crosstalk of lymphocytes with Hodgkin lymphoma cell lines. PLOS ONE. 8, e79502 (2013).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Kewitz, S. et al. Histone deacetylase inhibition restores cisplatin sensitivity of Hodgkin’s lymphoma cells. Leuk. Res. 36, 773–778 (2012).

    CAS  PubMed  Google Scholar 

  20. 20.

    Kretzner, L. et al. Combining histone deacetylase inhibitor vorinostat with aurora kinase inhibitors enhances lymphoma cell killing with repression of c-myc, hTERT, and microRNA levels. Cancer Res. 71, 3912–3920 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Bobrowicz, M. et al. HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies. Blood 130, 1628–1638 (2017).

    CAS  PubMed  Google Scholar 

  22. 22.

    Olsen, E. A. et al. Phase IIB multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T cell lymphoma. J. Clin. Oncol. 25, 3109–3115 (2007). This paper presents results from a phase II trial of the HDAC inhibitor vorinostat, leading to the first FDA approval of an HDAC inhibitor.

    CAS  PubMed  Google Scholar 

  23. 23.

    Whittaker, S. J. et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T cell lymphoma. J. Clin. Oncol. 28, 4485–4491 (2010). This paper presents results from the phase II trial of the HDAC inhibitor romidepsin, leading to its approval for CTCL.

    CAS  PubMed  Google Scholar 

  24. 24.

    Coiffier, B. et al. Results from a pivotal, open-label, phase II study of romidepsin relapsed or refractory peripheral T cell lymphoma after prior systemic therapy. J. Clin. Oncol. 30, 631–636 (2012). This paper presents results from the phase II trial of the HDAC inhibitor romidepsin, leading to its approval for PTCL.

    CAS  PubMed  Google Scholar 

  25. 25.

    O’Connor, O. A. et al. Belinostat in patients with relapsed or refractory peripheral T cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J. Clin. Oncol. 33, 2492–2499 (2015). This paper presents results from the phase II trial of the HDAC inhibitor belinostat, leading to its approval for PTCL.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    San-Miguel, J. F. et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma: a multicentre, randomized, double-blind phase 3 trial. Lancet Oncol. 15, 1195–1206 (2014).

    CAS  PubMed  Google Scholar 

  27. 27.

    Ogura, M. et al. A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B cell non-Hodgkin lymphoma and mantle cell lymphoma. Br. J. Haematol. 165, 768–776 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Kirschbaum, M. et al. Phase II study of vorinostat for treatment of relapsed or refractory indolent non-hodgkin’s lymphoma and mantle cell lymphoma. J. Clin. Oncol. 29, 1198–1203 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Younes, A. et al. Panobinostat in patients with relapsed/refractory hodgkin’s lymphoma after autologous stem-cell transplantation: results of a phase II study. J. Clin. Oncol. 30, 2197–2203 (2012). This paper presents results from a large clinical trial of panobinostat in patients with heavily pretreated HL who relapsed or were refractory to autologous transplant.

    CAS  PubMed  Google Scholar 

  30. 30.

    Zaja, F. et al. Single-agent panobinostat for relapsed/refractory diffuse large B cell lymphoma: clinical outcome and correlation with genomic data. A phase 2 study of the Fondazione Italiana Linfomi. Leuk. Lymphoma 59, 2904–2910 (2018).

    CAS  PubMed  Google Scholar 

  31. 31.

    Duvic, M. et al. Panobinostat activity in both bexarotene-exposed and naïve patients with refractory cutaneous T cell lymphoma: results of a phase II trial. Eur. J. Cancer 49, 386–394 (2013).

    CAS  PubMed  Google Scholar 

  32. 32.

    Ribrag, V. et al. Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia: results of a phase II study. Haematologica 102, 903–909 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Batlevi, C. et al. ENGAGE-501: phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphoma. Haematologica 101, 968–975 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Batlevi, C. et al. A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma. Br. J. Haematol. 178, 434–441 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Child, F. et al. Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA myclosis fungoides/Sezary syndrome. Br. J. Dermatol. 175, 80–88 (2016).

    CAS  PubMed  Google Scholar 

  36. 36.

    Shi, Y. et al. Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T cell lymphoma. Ann. Oncol. 26, 1766–1771 (2015).

    CAS  PubMed  Google Scholar 

  37. 37.

    Assouline, S. et al. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B cell lymphoma. Blood 128, 185–194 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Chen, R. et al. A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma. Haematologica 100, 357–362 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Tan, D. et al. Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T cell lymphoma: an open-label, multicentre phase 2 trial. Lancet Haematol. 2, e326–e333 (2015).

    PubMed  Google Scholar 

  40. 40.

    Lunning, M. A. et al. A phase I/II trial of the combination of romidepsin and lenalidomide in patients with relapsed/refractory lymphoma and myeloma: phase I results. J. Clin. Oncol. 32 (Suppl. 15), 8582 (2014).

    Google Scholar 

  41. 41.

    Amengual, J. E. et al. A phase I study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T cell lymphoma. Blood 131, 397–407 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Younes, A. et al. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase I trial. Lancet Oncol. 17, 622–631 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Perksy, D. O. et al. A phase I/II trial of vorinostat (SAHA) in combination with rituximab-CHOP in patients with newly diagnosed advanced stage diffuse large B cell lymphoma (DLBCL): SWOG S0806. Am. J. Hematol. 93, 486–493 (2018).

    Google Scholar 

  44. 44.

    Budde, L. E. et al. A phase I study of pulse high-dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma. Br. J. Haematol. 161, 183–191 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Hu, B. et al. Phase-I and randomized phase-II trial of panobinostat in combination with ICE (ifosfamide, carboplatin, etoposide) in relapsed or refractory classical Hodgkin lymphoma. Leuk. Lymphoma 59, 863–870 (2018).

    CAS  PubMed  Google Scholar 

  46. 46.

    Nieto, Y. et al. Vorinostat combined with high-dose gemcitabine, busulfan, and melphalan with autologous stem cell transplantation in patients with refractory lymphomas. Biol. Blood Marrow Transplant. 21, 1914–1920 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Dupuis, J. et al. Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T cell lymphoma: a non-randomised, phase Ib/2 study. Lancet Haematol. 2, e160–e165 (2015).

    PubMed  Google Scholar 

  48. 48.

    Chihara, D. et al. High response rate of romidepsin in combination with ICE (ifosfamide, carboplatin, and etoposide) in patients with relapsed or refractory peripheral T cell lymphoma: updates of phase I trial. Blood 126, 3987 (2015).

    Google Scholar 

  49. 49.

    Pfister, S. X. & Ashowrth, A. Marked for death: targeting epigenetic changes in cancer. Nat. Rev. Drug Discov. 16, 241–263 (2017).

    CAS  PubMed  Google Scholar 

  50. 50.

    Humphries, L. A. et al. Pro-apoptotic TP53 homolog TAp63 is repressed via epigenetic silencing and B cell receptor signaling in chronic lymphocytic leukemia. Br. J. Haematol. 163, 590–602 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Giachelia, M. et al. Quantification of DAPK1 promoter methylation in bone marrow and peripheral blood as a follicular lymphoma biomarker. J. Mol. Diag. 16, 467–476 (2014).

    CAS  Google Scholar 

  52. 52.

    Asmar, F. et al. Diffuse large B cell lymphoma with combined TP53 mutation and MIR34A methylation: another “double hit” lymphoma with very poor outcome? Oncotarget 5, 1912–1925 (2014).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Flinders, C. et al. Epigenetic changes mediated by polycomb repressive complex 2 and E2a are associated with drug resistance in a mouse model of lymphoma. Genome Med. 8, 54 (2016).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Leshchenko, V. et al. Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma. Blood 116, 1025–1034 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Nagasawa, T. et al. Multi-gene epigenetic silencing of tumor suppressor genes in T cell lymphoma cells; delayed expression of the p16 protein upon reversal of the silencing. Leuk. Res. 30, 303–312 (2006).

    CAS  PubMed  Google Scholar 

  56. 56.

    De, S. et al. Aberration in DNA methylation in B cell lymphomas has a complex origin and increases with disease severity. PLOS Genet. 9, 1003137 (2013).

    Google Scholar 

  57. 57.

    Wedge, E. et al. Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma. Am. J. Hematol. 92, 689–694 (2017).

    CAS  PubMed  Google Scholar 

  58. 58.

    Shaknovich, R. et al. DNA methylation signatures define molecular subtypes of diffuse large B cell lymphoma. Blood 116, e81–e89 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Alizadeh, A. et al. Distinct types of diffuse large B cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000). This seminal paper describes two molecularly distinct types of DLBCL, which are identified as GCB-like and activated B cell-like.

    CAS  PubMed  Google Scholar 

  60. 60.

    Oakes, C. et al. Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia. Cancer Discov. 4, 348–361 (2014).

    CAS  PubMed  Google Scholar 

  61. 61.

    Teater, M. et al. AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis. Nat. Commun. 9, 222 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Amara, K. et al. DNA methyltransferase DNMT3b protein overexpression as a prognostic factor in patients with diffuse large B cell lymphomas. Cancer Sci. 101, 1722–1730 (2010).

    CAS  PubMed  Google Scholar 

  63. 63.

    Robaina, M. et al. Deregulation of DNMT1, DNMT3B and miR-29s in Burkitt lymphoma suggests novel contribution for disease pathogenesis. Exp. Mol. Pathol. 98, 200–207 (2015).

    CAS  PubMed  Google Scholar 

  64. 64.

    Clozel, T. et al. Mechanism-based epigenetic chemosensitization therapy of diffuse large B cell lymphoma. Cancer Discov. 3, 1002–1019 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Chiappinelli, K. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015). This study demonstrates a mechanism of action of DNMT inhibitors that occurs through upregulation of immune signalling through a viral defence pathway.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Guo, Z. et al. De novo induction of a cancer/testis antigen by 5-aza-2′-deoxycytidine augments adoptive immunotherapy in a murine tumor model. Cancer Res. 66, 1105–1113 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Topper, M. et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. Cell 171, 1284–1300 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    National Comprehensive Cancer Network. Acute myeloid leukemia. NCCN https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf (2019).

  69. 69.

    Silverman, L. R. et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J. Clin. Oncol. 20, 2429–2440 (2002). This study demonstrates improved survival with azacitidine compared with best supportive care in patients with MDS, leading to its FDA approval.

    CAS  PubMed  Google Scholar 

  70. 70.

    Kantarjian, H. et al. Decitabine improves patient outcomes in myelodysplastic syndromes. Cancer 106, 1794–1780 (2006). This study demonstrates improved time to AML transformation with decitabine compared with best supportive care in patients with MDS, leading to its FDA approval.

    CAS  PubMed  Google Scholar 

  71. 71.

    Fenaux, P. et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J. Clin. Oncol. 28, 562–569 (2010).

    CAS  PubMed  Google Scholar 

  72. 72.

    Kantarjian, H. M. et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J. Clin. Oncol. 30, 2670–2677 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Malik, A. et al. Azacitidine in fludarabine-refractory chronic lymphocytic leukemia: a phase II study. Clin. Lymphoma Myeloma Leuk. 13, 292–295 (2013).

    CAS  PubMed  Google Scholar 

  74. 74.

    Blum, K. A. et al. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br. J. Haematol. 150, 189–195 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Fan, H. et al. Low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors: a phase I/II report. J. Immunol. Res. 2014, 371087 (2014).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Martin, P. et al. A phase I, open-label, multicenter trial of oral azacitidine (cc-486) plus R-CHOP in patients with high-risk, previously untreated diffuse large B cell lymphoma, grade 3B follicular lymphoma or transformed lymphoma. Blood 130, 192 (2017).

    Google Scholar 

  77. 77.

    Moss, J. J. et al. A phase I study of the combination of azactidine, cyclophosphamide, vincristine, and rituximab in relapsed and refractory lymphoma. Blood 118, 1624 (2011).

    Google Scholar 

  78. 78.

    Nieto, Y. et al. Double epigenetic modulation of high-dose chemotherapy with azacitidine and vorinostat for patients with refractory or poor-risk relapsed lymphoma. Cancer 122, 2680–2688 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Falchi, L. et al. A phase I/2 study of oral 5-azacitidine and romidepsin in patients with lymphoid malignancies reveals promising activity in heavily pretreated peripheral T cell lymphoma (PTCL). Blood 130, 1515 (2017).

    Google Scholar 

  80. 80.

    Pera, B. et al. Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients. Clin. Epigenetics 8, 79 (2016).

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Beguelin, W. et al. EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop. Nat. Commun. 8, 877 (2017).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Beguelin, W. et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677–692 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Caganova, M. et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J. Clin. Invest. 123, 5009–5022 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Bodor, C. et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood 122, 3165–3168 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Sneeringer, C. J. 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. USA 107, 20980–20985 (2010).

    CAS  PubMed  Google Scholar 

  86. 86.

    Beguelin, W. et al. EZH2 and BCL6 cooperate to assemble CBX8-BCOR complex to repress bivalent promoters, mediate germinal center formation and lymphomagenesis. Cancer Cell 30, 197–213 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Knutson, S. et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-hodgkin lymphoma. Mol. Cancer Ther. 13, 842–854 (2014).

    CAS  PubMed  Google Scholar 

  88. 88.

    Brach, D. et al. EZH2 inhibition by tazemetostat results in altered dependency on B cell activation signaling in DLBCL. Mol. Cancer Ther. 16, 2586–2597 (2017).

    CAS  PubMed  Google Scholar 

  89. 89.

    Oricchio, E. et al. Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma. Sci. Transl Med. 9, 9969 (2017).

    Google Scholar 

  90. 90.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Zhang, J. et al. The genetic basis of early T cell precursor acute lymphoblastic leukemia. Nature 481, 157–163 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Danis, E. et al. EZH2 controls an early hematopoietic program and growth and survival signaling in early T cell precursor acute lymphoblastic leukemia. Cell Rep. 14, 1953–1965 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    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. 19, 649–659 (2018). This is the first published study reporting results from the first-in-human phase I trial of the EZH2 inhibitor tazemetostat.

    CAS  PubMed  Google Scholar 

  94. 94.

    Yap, T. et al. A phase I, open-label study of GSK2816126, an enhancer of zeste homolog 2(EZH2) inhibitor, in patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL), trasnformed follicular lymphoma (tFL), other non-Hodgkin’s lymphomas (NHL), multiple myeloma (MM) and solid tumors [abstract]. J Clin. Oncol. 34 (Suppl. 15), TPS2595 (2016).

    Google Scholar 

  95. 95.

    Maruyama, D. et al. First-in-human study of the EZH1/2 dual inhibitor DS-3201b in patients with relapsed or refractory non-hodgkin lymphomas – preliminary results. Blood 130, 4070 (2017).

    Google Scholar 

  96. 96.

    Morschhauser, F. et al. Interim report from a phase 2 multicenter study of tazemetostat, and EZH2 inhibitor, in patients with relapsed or refractory B cell non-hodgkin lymphomas. Hematol. Oncol. 34, 24–25 (2017).

    Google Scholar 

  97. 97.

    Morschhauser, F. et al. Interim update from a phase 2 multicenter study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory (R/R) follicular lymphoma (FL). Clin. Lymphoma Myeloma Leuk. 18 (Suppl. 1), 278–279 (2018).

    Google Scholar 

  98. 98.

    Honma, D. et al. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 108, 2069–2078 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Shortt, J. et al. A chemical probe toolbox for dissecting the cancer epigenome. Nat. Rev. Cancer 160, 160–182 (2017).

    Google Scholar 

  100. 100.

    Doroshow, D. B. & LoRusso, P. M. BET inhibitors: a novel epigenetic approach. Ann. Oncol. 28, 1776–1787 (2017).

    CAS  PubMed  Google Scholar 

  101. 101.

    Ozer, H. G. et al. BRD4 profiling identifies critical chronic lymphocytic leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor. Cancer Discov. 8, 458–477 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Vazquez, R. et al. The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus. Oncotarget 8, 7598–7613 (2017).

    PubMed  Google Scholar 

  103. 103.

    Wang, L. et al. BRD4 inhibitor IBET upregulates p27kip/cip protein stability in neuroendocrine tumor cells. Cancer Biol. Ther. 18, 229–236 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Yokoyama, Y. et al. BET inhibitors suppress ALDH activity by targeting ALDH1A1 super-enhancer in ovarian cancer. Cancer Res. 76, 6320–6330 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Piunti, A. et al. Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas. Nat. Med. 23, 493–500 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Gryder, B. E. et al. PAX3-FOX01 establishes myogenic super enhancers and confers BET bromodomain vulnerability. Cancer Discov. 7, 884–899 (2017).

    CAS  PubMed  Google Scholar 

  107. 107.

    Loven, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Esteve-Arenys, A. et al. The BET bromodomain inhibitor CPI203 overcomes resistance to ABT-199 (venetoclax) by downregulation of BFL-1/A1 in in vitro and in vivo models of MYC+/BCL2+ double hit lymphoma. Oncogene 37, 1830–1844 (2018).

    CAS  PubMed  Google Scholar 

  109. 109.

    Sun, B. et al. BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells. Leukemia 32, 343–352 (2018).

    CAS  PubMed  Google Scholar 

  110. 110.

    Kohnken, R. et al. Diminished microRNA-29b level is associated with BRD4-mediated activation of oncogenes in cutaneous T cell lymphoma. Blood 131, 771–781 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    He, A. et al. JQ1 reduces Epstein-Barr virus-associated lymphoproliferative disease in mice without sustained oncogene repression. Leuk. Lymphoma 59, 1248–1251 (2017).

    PubMed  Google Scholar 

  112. 112.

    Gopalakrishnan, R. et al. Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors. Oncogene 35, 1797–1810 (2016).

    CAS  PubMed  Google Scholar 

  113. 113.

    Hogg, S. J. et al. BET inhibition induces apoptosis in aggressive B cell lymphoma via epigenetic regulation of BCL-2 family members. Mol. Cancer Ther. 15, 2030–2041 (2016).

    CAS  PubMed  Google Scholar 

  114. 114.

    Amorim, S. et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Hematol. 3, e196–e204 (2016). This is the first published study reporting results from a phase I trial of the BET inhibitor OTX015.

    Google Scholar 

  115. 115.

    Abramson, J. S. et al. BET inhibitor CPI-0610 is well tolerated and induces responses in diffuse large B cell lymphoma and follicular lymphoma: preliminary analysis of an ongoing phase I study. Blood 126, 1491 (2015).

    Google Scholar 

  116. 116.

    Forero-Torres, A. et al. Preliminary results from an ongoing phase I/II study of INCB057643, a bromodomain and extraterminal (BET) protein inhibitor, in patients with advanced malignancies. Blood 130, 4048 (2017).

    Google Scholar 

  117. 117.

    Postel-Vinay, S. et al. First-in-human phase I dose escalation study of the bromodomain and extra-terminal motif (BET) inhibitor BAY 1238097 in subjects with advanced malignancies. Eur. J. Cancer 69 (Suppl. 1), 7–8 (2016).

    Google Scholar 

  118. 118.

    Falchook, G. et al. Phase I/II study of INCB054329, a bromodomain and extraterminal (BET) protein inhibitor in patients with advanced malignancies [abstract]. Mol. Cancer Ther. 17 (Suppl. 1), A093 (2018).

    Google Scholar 

  119. 119.

    Dickinson, M. et al. A phase I study of molibresib (GSK525762), a selective bromodomain (BRD) and extra terminal protein (BET) inhibitor: results from part 1 of a phase I/II open label single agent study in subjects with non-hodgkin’s lymphoma (NHL) [abstract]. Blood 132, 1682 (2018).

    Google Scholar 

  120. 120.

    Alinari, L. et al. Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B cell transformation. Blood 125, 2530–2543 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Koh, C. M. et al. MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature 523, 96–100 (2015).

    CAS  PubMed  Google Scholar 

  122. 122.

    Lu, X. et al. PRMT5 interacts with BCL6 oncoprotein and is required for germinal center formation and lymphoma cell survival. Blood 132, 2026–2039 (2018). In this study, the authors show that PRMT5 interacts with BCL-6 in germinal centre formation and that concurrent targeting of both enzymes leads to synergistic killing of lymphoma cells.

    CAS  PubMed  Google Scholar 

  123. 123.

    Pal, S. et al. Low levels of miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma. EMBO J. 26, 3558–3569 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Yan, F. et al. Developing a novel class of drug to inhibit protein arginine methyltransferase 5 (PRMT5) enzyme dysregulation in mantle cell lymphoma. Blood 118, 595 (2011).

    Google Scholar 

  125. 125.

    Chan-Penebre, E. et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat. Chem. Biol. 11, 432–437 (2015). This paper presents preclinical data for a novel PRMT5 inhibitor in MCL cell lines and in MCL xenograft mouse models.

    CAS  PubMed  Google Scholar 

  126. 126.

    Panfil, A. R. et al. PRMT5 is upregulated in HTLV-1-mediated T cell transformation and selective inhibition alters viral gene expression and infected cell survival. Viruses 8, 7 (2015).

    PubMed Central  Google Scholar 

  127. 127.

    Li, Y. et al. PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers. Cancer Discov. 5, 288–303 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Nguyen, T. B. et al. Identification of cell-type-specific mutations in nodal T cell lymphomas. Blood Cancer J. 7, e516 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Sakata-Yamagimoto, M. et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 171–175 (2014).

    Google Scholar 

  131. 131.

    Wang, C. et al. IDH2 R172 mutations define a unique subgroup of patients with angioimmunoblastic T cell lymphoma. Blood 126, 1741–1752 (2015). This study demonstrates that IDH2 R172 mutations define a unique phenotype in AITL with repression of genes involved with T cell receptor signalling and T cell differentiation, leading to lymphomagenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Lemonnier, F. et al. The IDH2 R172K mutation associated with angioimmunoblastic T cell lymphoma produces 2HG in T cells and impacts lymphoid development. Proc. Natl Acad. Sci. USA 113, 15084–15089 (2016).

    CAS  PubMed  Google Scholar 

  133. 133.

    Van Damme, M. et al. Characterization of TET and IDH gene expression in chronic lymphocytic leukemia: comparison with normal B cells and prognostic significance. Clin. Epigenetics 8, 132 (2016).

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Stein, E. M. et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 136, 722–731 (2017). This paper presents results from the phase I/II trial of the IDH2 inhibitor enasidenib, leading to its FDA approval for IDH2 -mutant AML.

    Google Scholar 

  135. 135.

    DiNardo, C. D. et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N. Engl. J. Med. 378, 2386–2398 (2018). This paper presents results from the phase I trial of the IDH1 inhibitor ivosidenib, leading to its FDA approval for IDH1 -mutant AML.

    CAS  PubMed  Google Scholar 

  136. 136.

    Fathi, A. T. et al. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2. JAMA Oncol. 4, 1106–1110 (2018).

    PubMed  Google Scholar 

  137. 137.

    Intlekofer, A. M. et al. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature 559, 125–129 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Boi, M. et al. The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B cell tumor models and synergizes with targeted drugs. Clin. Cancer Res. 21, 1628–1638 (2015).

    CAS  PubMed  Google Scholar 

  139. 139.

    Bernasconi, E. et al. Preclinical evaluation of the BET bromodomain inhibitor BAY1238097 for the treatment of lymphoma. Br. J. Haematol. 178, 936–948 (2017).

    CAS  PubMed  Google Scholar 

  140. 140.

    Schaffer, M. et al. Identification of potential ibrutinib combinations in hematological malignancies using a combination high-throughput screen. Leuk. Lymphoma 59, 931–940 (2018).

    CAS  PubMed  Google Scholar 

  141. 141.

    Gaudio, E. et al. Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma. Oncotarget 7, 58142–58147 (2016).

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Muralidharan, S. V. et al. BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in MYC-induced lymphoma cells. Oncogene 35, 4689–4697 (2016).

    CAS  PubMed  Google Scholar 

  143. 143.

    Swerev, T. M. et al. Activation of oncogenic pathways in classical Hodgkin lymphoma by decitabine: a rationale for combination with small molecular weight inhibitors. Int. J. Oncol. 50, 555–566 (2017).

    CAS  PubMed  Google Scholar 

  144. 144.

    Cycon, K. A. et al. Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B cell lymphoma. Immunology 140, 259–272 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Tiper, I. V. et al. Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma. Cancer Immunol. Immunother. 65, 1411–1421 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Ghoneim, H. E. et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170, 142–157 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Lai, Q. et al. Decitabine improves the efficiency of anti-PD-1 therapy via activating the response to IFN/PD-L1 signal of lung cancer cells. Oncogene 37, 2302–2312 (2018).

    CAS  PubMed  Google Scholar 

  148. 148.

    Zhang, J. et al. Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nat. Med. 21, 1190–1198 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Ortega-Molina, A. et al. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat. Med. 21, 1199–1208 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Sakata-Yanagimoto, M. et al. Detection of the circulating tumor DNAs in angioimmunoblastic T cell lymphoma. Ann. Hematol. 96, 1471–1475 (2017).

    CAS  PubMed  Google Scholar 

  151. 151.

    Pixberg, C. F. et al. Analysis of DNA methylation in single circulating tumor cells. Oncogene 36, 3223–3231 (2017).

    CAS  PubMed  Google Scholar 

  152. 152.

    Puvvada, S. et al. A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B cell lymphomas: SWOG S0520. Leuk. Lymphoma 57, 2359–2369 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Dummer, R. et al. Vorinostat combined with bexarotene for treatment of cutaneous T cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition. Leuk. Lymphoma 53, 1501–1508 (2012).

    CAS  PubMed  Google Scholar 

  154. 154.

    Oki, Y. et al. Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clin. Cancer Res. 19, 6882–6890 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge financial support from the US National Institutes of Health (NIH) (NIH P50 CA192937 (MSK Lymphoma SPORE) to L.P., A.M. and A.Y. and NIH 2R01-CA172492-06A1 to L.P.); the Leukaemia and Lymphoma Society of America SCOR grant 7014–17 (to A.Y.); the US National Cancer Institute, Cancer Center Support Grant P30 CA008748 (to A.Y.); and the Cycle for Survival and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology.

Author information

Affiliations

Authors

Contributions

All authors made a substantial contribution to all aspects of the preparation of this manuscript.

Corresponding author

Correspondence to Anas Younes.

Ethics declarations

Competing interests

L.P. receives research support from Sanofi. A.M. has received consultancy fees and research support from Janssen. A.Y. has received honoraria and/or consultancy fees from Abbvie, Biopath, Curis, Epizyme, Janssen, Merck, Roche, Takeda and Xynomic and has received research support from Bristol-Myers Squibb, Curis, Janssen, Merck, Roche and Syndax. The other authors declare no competing interests.

Additional information

Publisher’s note

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sermer, D., Pasqualucci, L., Wendel, HG. et al. Emerging epigenetic-modulating therapies in lymphoma. Nat Rev Clin Oncol 16, 494–507 (2019). https://doi.org/10.1038/s41571-019-0190-8

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing