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Review
. 2015 Feb 19;125(8):1217-25.
doi: 10.1182/blood-2014-10-606822. Epub 2015 Jan 7.

Polycomb genes, miRNA, and their deregulation in B-cell malignancies

Gang Greg Wang  1 , Kyle D Konze  2 , Jianguo Tao  3
Affiliations
Review

Polycomb genes, miRNA, and their deregulation in B-cell malignancies

Gang Greg Wang et al. Blood. .

Abstract

Posttranslational modifications of histone proteins represent a fundamental means to define distinctive epigenetic states and regulate gene expression during development and differentiation. Aberrations in various chromatin-modulation pathways are commonly used by tumors to initiate and maintain oncogenesis, including lymphomagenesis. Recently, increasing evidence has demonstrated that polycomb group (PcG) proteins, a subset of histone-modifying enzymes known to be crucial for B-cell maturation and differentiation, play a central role in malignant transformation of B cells. PcG hyperactivity in B-cell lymphomas is caused by overexpression or recurrent mutations of PcG genes and deregulation of microRNAs (miRNAs) or transcription factors such as c-MYC, which regulate PcG expression. Interplays of PcG and miRNA deregulations often establish a vicious signal-amplification loop in lymphoma associated with adverse clinical outcomes. Importantly, aberrant enzymatic activities associated with polycomb deregulation, notably those caused by EZH2 gain-of-function mutations, have provided a rationale for developing small-molecule inhibitors as novel therapies. In this review, we summarize our current understanding of PcG-mediated gene silencing, interplays of PcG with other epigenetic regulators such as miRNAs during B-cell differentiation and lymphomagenesis, and recent advancements in targeted strategies against PcG as promising therapeutics for B-cell malignancies.

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Figures

Figure 1
Figure 1
Cooperation of PRC2 and PRC1 in epigenetic silencing of genes. PRC2 catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3) (A), which is recognized and bound by CBX proteins such as CBX7, a PRC1 subunit, to subsequently recruit PRC1 for induction of monoubiquitination of histone H2A at lysine 119 (H2AK119ub1), (B).Conversely, recent studies show that a variant form of PRC1 can act upstream of PRC2 to initiate formation of the polycomb domain; in this case, H2AK119ub1 serves as a PRC2 recruitment mechanism (C).- In addition, EED is also shown to interact to PRC1 physically. CpG, cytosine guanine dinucleotide; Me, trimethylation; Ub, ubiquitination.
Figure 2
Figure 2
Biological functions of EZH2 in normal B-cell development and lymphomagenesis. During B-cell differentiation, naive B cells enter the GC and EZH2 is transcriptionally upregulated during GC B-cell maturation., Via induction of H3K27me3, EZH2 then transcriptionally represses a myriad of downstream effector genes, which at least include the negative cell-cycle regulators (CDKN2A and CDKN1A) and B-cell differentiation-promoting transcription factors (IRF4 and BLIMP1/PRDM1), hence allowing for rapid expansion of immature B cells,,; in addition, EZH2 protects GC B cells from the genotoxic damages induced by activation-induced cytidinedeaminase (AID), an enzyme critical for immunoglobulin affinity maturation via a mechanism of somatic hypermutation that modifies the immunoglobulin variable region of the rearranged antibody genes in GC B cells. EZH2 levels decrease as B cells exit the GC, enabling derepression of EZH2-targeted genes and hence terminal differentiation.,, However, EZH2 hyperactivity (either somatic mutation or overexpression) disrupts such fine equilibrium, continuously enhances H3K27me3, and results in exaggerated silencing of EZH2 targeted genes, which then block GC B-cell differentiation and promote their proliferation and survival. EZH2 mutations alone lead to follicular hyperplasia, and, with acquisition of additional oncogenic events such as upregulation of BCL2 or c-MYC, EZH2 mutations cooperatively enable or accelerate malignant transformation of GC B cells.,
Figure 3
Figure 3
Vicious amplification loops involving a myriad of PcG proteins and miRNAs. Repression of PRC1-repressing miRNAs by PRC2 (A) establishes a positive-feedback loop ensuring coexpression and cooperation of 2 main PcG repressor complexes in stem and cancer cells; c-MYC, which is frequently translocated or overexpressed in Burkitt lymphoma and other B-cell lymphoma types, assembles a gene-silencing complex with PRC2 and HDACs to downregulate a list of tumor-suppressive miRNAs that can repress EZH2 and DNMT3A (B), hence establishing positive-feedback loops to enforce expression and functionality of PRC2 in B-cell lymphomas. Me3, trimethylation. Ub1, mono-ubiquitination.
Figure 4
Figure 4
Highly selective, small-molecule inhibitors of PRC2. (A) Scaffold demonstrating that several of the recently developed EZH2 or EZH2/1 inhibitors all possess a pyridone motif as well as an indole or indazole core. The inserted table details the identity of each designated substituent of the described inhibitors. (B) Chemical structure of EPZ-6438. (C) Chemical structure of Constellation Pharmaceuticals compound 3, the first non–pyridone-containing EZH2 inhibitor.
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