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3 Epigenetics of T‐cell Lymphoma
H. Miles Prince1, Jasmine Zain2, Anas Younes3, Sean Whittaker4, Owen A. O’Connor5, 6 and Sean Harrop7
1 Epworth Healthcare and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
2 Department of Hematology/Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA
3 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
4 Guy’s and St Thomas’ National Health Service Foundation Trust, London, UK
5 Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA
6 Program for T‐Cell Lymphoma Research, Department of Microbiology, Immunology and Cancer Research, University of Virginia Cancer Center, Charlottesville, VA, USA
7 Epworth Healthcare and Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
TAKE HOME MESSAGES
Epigenetic alterations play a significant role in T‐cell lymphomas, largely through DNA methylation and histone modification that result in changes in gene expression.
Mutations resulting in gain and loss of function of epigenetic genes are seen in varying frequency and different combinations across the different subsets of T‐cell lymphomas.
These genetic derangements are attractive therapeutic targets. The efficacy of single agents that target the epigenome is well established and rational combinations offer a paradigm changing approach to management.
Introduction
There is no other disease for which the constellation of data and evidence points toward the conclusion that T‐cell lymphomas (TCLs) may represent the prototypical malignant disease characterized by gross epigenetic derangements and vulnerability. This sentiment is driven by a number of observations. First, around the world, there are now four histone deacetylases (HDACs) approved as single agents for the disease. These drugs appear to exhibit a class effect and, at least as single agents, have yet to demonstrate the same degree of clinical benefit in any other disease. Second, emerging data have identified a host of derangements in important epigenetic genes which play a critical role in governing gene transcriptions. These genes, including but not limited to DNMT3, IDH2, and TET2 for example, can profoundly alter DNA methylation, though these derangements are not prevalent across all subtypes of peripheral TCL (PTCL). Third, several experimental lines of evidence suggest that combinations of select mutated epigenetic genes, like TET2, coupled with recurring mutations in RhoA, can recapitulate certain types of TCL, in particular angioimmunoblastic TCL (AITL). Last, combinations of drugs targeting various epigenetic derangements predicated on HDAC inhibitors and hypomethylating agents (HMA), are producing responses and durations of response that appear promising. Synthesizing and interpreting these seemingly divergent lines of data are likely to offer an unprecedented opportunity to leverage this unique biology and pharmacology to in a manner which can have important impact on our ability to diagnose, prognosticate and ultimately treat these challenging diseases. Below, we review these data, and describe how this information may be used to better understand the T‐cell malignancies.
Epigenetic Pathways Altered in T‐cell Lymphoma
Neoplasias have a distinct pattern of disrupted pathways, which are the result not only of genetic alterations, but also of heritable patterns of disrupted gene expression. Epigenetics refers to these clonal changes in patterns of gene expression that are mediated by mechanisms that do not alter the primary DNA sequence. Epigenetic changes in tumors mostly result in inappropriate gene silencing and effect a diverse variety of cellular functions, often affecting the tumor itself and its interaction with the microenvironment and immune response [1].
Epigenetic changes generally are the result of two processes: (i) DNA methylation (DNA global hypomethylation and promoter‐localized hypermethylation) and (ii) histone modifications. The proteins responsible for the alterations characteristic of the cancer epigenome are the enzymes that catalyze DNA methylation, the proteins that bind methylated DNA at promoters and contribute to transcriptional silencing, and the chromatin modifier enzymes that catalyze histone acetylation, deacetylation, methylation, and demethylation.
Adding another layer of complexity, not only can gene transcription be altered within the abnormal cell by abnormal changes in these processes, cancers can harbor specific
