Abstract
Polycomb repressive complexes (PRCs) are epigenetic regulators that mediate repressive histone modifications. PRCs play a pivotal role in the maintenance of hematopoietic stem cells through repression of target genes involved in cell proliferation and differentiation. Next-generation sequencing technologies have revealed that various hematologic malignancies harbor mutations in PRC2 genes, such as EZH2, EED, and SUZ12, and PRC1.1 genes, such as BCOR and BCORL1. Except for the activating EZH2 mutations detected in lymphoma, most of these mutations compromise PRC function and are frequently associated with resistance to chemotherapeutic agents and poor prognosis. Recent studies have shown that mutations in PRC genes are druggable targets. Several PRC2 inhibitors, including EZH2-specific inhibitors and EZH1 and EZH2 dual inhibitors have shown therapeutic efficacy for tumors with and without activating EZH2 mutations. Moreover, EZH2 loss-of-function mutations appear to be attractive therapeutic targets for implementing the concept of synthetic lethality. Further understanding of the epigenetic dysregulation associated with PRCs in hematological malignancies should improve treatment outcomes.
Highlights
Polycomb repressive complexes (PRCs) are composed of polycomb group (PcG)proteins and are epigenetic regulators that mediate repressive histone modifications [1].There are two major types of PRCs, PRC1 and PRC2
Canonical PRC1 consists of polycomb group ring finger (PCGF) 4/BMI1 or PCGF2/MEL18, RING1A or RING1B, CBX, and PHC
We demonstrated that a Bcor mutant that lacks the PCGF1-binding domain combines with Tet2 loss to induce lethal myelodysplastic syndrome (MDS) in mice
Summary
Proteins and are epigenetic regulators that mediate repressive histone modifications [1]. EZH1/2 has specific histone methylation activity and mediates the mono-, di-, and trimethylation of H3 at lysine 27 (H3K27me1/me2/me3) (Figure 1) [2]. PRC1 binds to H3K27me through one of its components, CBX, and monoubiquitinates H2AK119. These histone modifications inhibit transcription and induce chromatin aggregation, which maintains transcriptional repression of target genes. 1. Polycomb repressive complexes (PRCs) are are multiprotein complexes thatthat playplay important multiprotein complexes important roles in the repression of target genes through chromatin modifications. PRC components thatthat are are roles in the repression of target genes through chromatin modifications. PRC components targeted by somatic gene mutations are indicated by stars. Black T arrow indicates inhibition of targeted by somatic gene mutations are indicated by stars.
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