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Prevalent Epigenetic Modifier Mutations Found in Follicular Lymphoma

Simoneaux, Richard

doi: 10.1097/01.COT.0000549776.96301.80
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Follicular lymphoma (FL), which is classified as an indolent malignancy, is the most common form of non-Hodgkin lymphoma (NHL), comprising roughly 20 percent of those cases. The management of this disease has been greatly aided by the addition of the CD20-targeting monoclonal antibody rituximab to patients' regimens, resulting in 5-year survival rates that approach 90 percent.

Despite this success, for two distinct subpopulations of FL patients, there remain difficulties. The first group of patients (roughly 20%) experience disease progression or relapses within 2 years after receiving their first-line therapy. The second group, which accounts for roughly 10-20 percent of FL cases, has disease that eventually undergoes a transformation (tFL) to a more aggressive form of malignancy such as diffuse large B-cell lymphoma (DLBCL).

In a recent review, Jude Fitzgibbon, PhD, Professor of Personalised Cancer Medicine, and Koorosh Korfi, PhD, a senior postdoctoral scientist, both at Barts Cancer Institute, Queen Mary University of London, and their colleagues discussed the mutations of epigenetic regulators that for 5 years or more now have been recognized as a frequent hallmark of FL (Epigenetics 2017;12(5):370-377).

“The most significant shift in our understanding of FL's genetic landscape has occurred following the application of advanced next-generation sequencing (NGS) techniques,” Fitzgibbon stated.

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Follicular Lymphoma Background

As a disease state, FL originates from germinal center (GC) B cells located within lymphoid tissues. While the vast majority of FL cases (85-90%) are characterized by the t(14;18) translocation, this genetic anomaly, in isolation, is not sufficient to cause disease; indeed, this rearrangement is present in perhaps 25 percent of healthy individuals who only in very rare cases develop this disease. This translocation results in BCL2 overexpression, which arises from IgH locus-based transcriptional control.

“Interestingly,” Fitzgibbon noted, “for the 10-15 percent of FL patients not having this translocation, the precise oncogenic drivers specific for their disease remain largely undetermined.”

As previously stated, FL is distinguished by its inherent abundance of mutations to epigenetic modifiers in almost all cases. “In direct contrast,” Fitzgibbon stated, “in the more aggressive DLBCL, mutations in epigenetic modifiers such as CREBBP, EP300, EZH2, and KMT2D occur in roughly 60 percent of the GC B-cell-like subtype, which shares a common cell of origin with FL. Fewer epigenetic mutations are reported in the activated B-cell-like subtype and Burkitt lymphoma, an even rarer form of GC NHL.”

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Common FL Mutations

Much knowledge has been gained regarding the mutations occurring in FL as a result of applying NGS techniques. “Many of the common mutations found are in genes that influence immune surveillance, with rarer mutations targeting B-cell development, BCR-NFkB, and JAK/STAT signaling pathways,” Fitzgibbon explained. “Most strikingly, several mutations have been identified in a series of epigenetic modifiers, such as CREBBP, EP300, EZH2, KMT2D, MEF2B; several members of SWI/SNF nucleosome remodeling complex (e.g., ARID1A, ARID1B, and BCL7A), as well as members of the linker histone H1 and histone H2 gene families.”

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Common Progenitor Cells & Transformed FL

Increasingly, the relapsing-remitting nature of FL is accounted for by the presence of a pool of long-lived B-cell progenitor cells (CPCs). “The profiling of both FL and tFL at different time points, and also, rare examples of donor-derived FL occurring several years following allogeneic stem cell transplant and donor lymphocyte infusions (i.e., both patients have the same IGH and IGH-BCL2 rearrangements and somatic mutations), lend plausibility for there being a reservoir of long-lived CPCs which act as tumor-initiating cells that need to be eliminated to improve outcomes,” Fitzgibbon explained.

The transformation of FL to a more aggressive lymphoma is thought to occur via divergent evolution, instead of by sequentially acquired genetic aberrations, as the presence of mutations affecting epigenetic modifiers (e.g., CREBBP, EZH2, KMT2D, and MEF2B) is noted in both FL and tFL samples.

“These mutations, which are typically clonal, support a founder role for these events in FL, while mutations in NFkB signaling pathway, B-cell development, or cell cycle genes tend to occur subsequently, as events presumably leading to the emergence of more viable clones that then drive disease progression and transformation. However, we have still much to learn,” Fitzgibbon clarified.

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Potential Targeted Therapies

HDAC Inhibitors

High-risk FL patients have an association with loss-of-function mutations to CREBBP/EP300 that lead to an acetylation imbalance, thus providing rationale for the use of histone deacetylase (HDAC) inhibitors in this subpopulation. Recent preclinical research showed that the loss of CREBBP in mice made the development of GC-derived lymphomas more likely (Cancer Discov 2017;7(1):38-53).

Both human and mouse-based lymphomas with CREBBP loss-of-function had depleted histone H3 lysine 27 (H3K27) acetylation and anomalous silencing of regulatory genes for B-cell signaling and immune responses. Repression of these enhancers and the pertinent genes were rescued by HDAC3 loss-of-function. Importantly, this loss-of-function also provided effective suppression of CREBBP-mutated lymphomas in vitro and in vivo.

These preclinical results would seem to imply that CREBBP loss-of-function facilitates lymphomagenesis by permitting unopposed suppression of enhancers by the deacetylating BCL6/SMRT/HDAC3 complexes. Thus, therapeutic strategies that counteract this disabled acetylation, such as HDAC3 inhibition, may be viable targeted therapies for those with CREBBP-mutant lymphomas.

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Lysine Demethylase Inhibitors

Although more than 80 percent of all FL patients have mutations to their lysine methyltransferase 2D (KMT2D) gene, no attempts have been made to exploit this genetic anomaly. Consequently, one potential therapeutic strategy to treat FL that the Fitzgibbon group is exploring may be the use of lysine demethylase (KDM) inhibitors that regulate histone 3 lysine 4 (H3K4) methylation. These inhibitors counteract the H3K4 methylation imbalance that occurs in loss-of-function KMT2D mutants. There are seven subfamilies of KDMs, however, only the KDM1 and KDM5 families regulate H3K4 methylation.

“There are a number of KDM1 and KDM5 inhibitors, although these have not been investigated in GC lymphoma,” Fitzgibbon noted. “More recently, potent KDM5 inhibitors have been evaluated in pre-clinical studies and showed encouraging inhibition of cell proliferation in myeloma and drug-resistant small cell lung cancer.

“Given these reports, it would seem that there may be value in exploring the use of KDM5 inhibitors as a potential therapy for patients with KMT2D-mutant FL,” Fitzgibbon concluded.

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EZH2 Inhibitors

Approximately 25 percent of FL patients have EZH2 gain-of-function mutations that function as oncogenic drivers and remain stable during disease relapse and/or transformation, therefore providing a valid therapeutic target.

“Several S-adenosylmethionine-competitive EZH2-selective inhibitors have been recently developed, including GSK-126, EPZ-6438, and CPI-1205, which display superior EZH2 selectivity over EZH1 and other histone methyltransferases,” Fitzgibbon stated. “In preclinical studies, these targeted therapies have shown significant inhibitory effects, particularly against EZH2-mutant lymphoma cell growth and survival; currently, they are being evaluated in phase I/II clinical trials.”

An objective response rate (i.e., partial or complete response) of 60 percent was obtained for a small subset of B-NHL patients in preliminary trial results of EPZ-6438 (Nat Med 2016;22:128-134).

Recent studies have also highlighted another potential use for EZH2 inhibitors, a means of eliminating cancer stem cells. “This concept appears to have some merit, as leukemic stem cells for chronic myeloid leukemia, which are typically resistant to first-line tyrosine kinase inhibitors, are sensitive to EZH2 inhibition due to their abnormal EZH2 gain-of-function status,” Fitzgibbon explained. “Therefore, it may be worth testing the efficacy of EZH2 inhibitors to target the subset of EZH2-mutant FL CPCs in order to prevent them from repopulating subsequent disease relapses or transformation.”

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Discussion

“The use of epigenetic therapies would appear to be warranted, as the mutations to epigenetic modifiers found in FL that arise in CPCs remain reasonably stable throughout the course of disease progression and transformation,” Fitzgibbon stated. “Our understanding of abnormal epigenetic mechanisms in FL is still at a very early stage and there are several hurdles to overcome if the epigenetic therapies are to realize their full potential clinically.

“Biologically, we need a better understanding on whether the mutated epigenetic modifiers act alone or in concert to drive B-cell malignancy and what functional impact they have on downstream pathways; therapeutically, future research efforts should focus on determining how these epigenetic therapies exert their effects in patients and determine treatment combinations that maximize their efficacy.

“Understandably, current therapeutic strategies for FL are based on a ‘one-size-fits-all’ approach that fails to account for the specific genetic and epigenetic aberrations in different patients,” Fitzgibbon noted. “Going forward, with a better understanding of how these mutations exert their effects, a more customized approach may be most beneficial for high-risk patients who relapse within the first 2 years and those whose FL undergoes transformation to a more aggressive lymphoma.

“The prevalence and apparent co-founding role of genetic mutations that alter epigenetic modification, together with the reversibility of epigenetic abnormalities, would seem to present an opportunity for targeting in a precision medicine approach that is worth pursuing.”

Richard Simoneaux is a contributing writer.

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