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.
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.
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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.
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.
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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
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