EZH2 in normal hematopoiesis and hematological malignancies

Abstract

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, inhibits gene expression through methylation on lysine 27 of histone H3. EZH2 regulates normal hematopoietic stem cell self-renewal and differentiation. EZH2 also controls normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. Specific small molecules have been recently developed to exploit the oncogenic addiction of tumor cells to EZH2. Their therapeutic potential is currently under evaluation. This review summarizes the roles of EZH2 in normal and pathologic hematological processes and recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies.

Keywords: EZH2; Polycomb complex; hematological malignancies; therapeutic target.

Figure 1. Polycomb complex-mediated transcription repression

Polycomb Repressive Complex 2 (PRC2) contains four core components. EZH2 (Enhancer-of-zeste homolog 2) is the catalytic sub-unit, whereas EED (Embryonic Ectoderm Development), SUZ12 (zinc finger) and RBAP46/48 (Retinoblastoma Binding Protein) contribute to improving EZH2 activity. PRC2 induces EZH2-mediated H3K27 tri-methylation (H3K27me3) to repress its target genes. The H3K27me3 mark is recognized by the CBX subunit of Polycomb Repressive Complex 1 (PRC1). Then, the E3 ubiquitin-protein ligase RING1A ubiquitinylates histone H2A at lysine 119, strengthening gene transcription repression.

Figure 2. EZH2 mutations in hematological malignancies

EZH2 has several functional domains: the WD-40 binding domain (WDB) that interacts with EED; domain 1 (D1); domain 2 (D2) that interacts with SUZ12; the domains SWI3, ADA2, N-CoR and TFIIIB (SANT) that interact with histones; a cysteine-rich domain (CXC); and the suppressor of variegation 3-9, enhancer of zeste and trithorax (SET) catalytic domain. Several EZH2 mutations have been identified in different hematological malignancies: lymphoma (purple star), myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) (blue stars) and T-cell acute lymphoblastic lymphoma (T-ALL) (orange stars).

Figure 3. EZH2 biological functions during normal B-cell differentiation and lymphomagenesis

During normal B-cell differentiation, EZH2 expression is induced when naive B-cells enter the germinal center for affinity maturation and antibody class switching. Through H3K27 tri-methylation, EZH2 represses the expression of negative cell cycle regulators (CDKN2A and CDKN1A) and of B- cell differentiation transcription factors (BLIMP1 and IRF4), leading to immature B-cell expansion. EZH2 also inhibits DNA damage response pathways, allowing survival of B-cells during AID-mediated somatic hypermutation of Ig genes. EZH2 expression decreases when B-cells exit the germinal centers, leading to de-repression of EZH2 target genes to support plasma cell maturation. Conversely, activating mutations or EZH2 overexpression lead to an imbalance due to increased repression of EZH2 target genes, induction of proliferation and blockade of B-cell maturation. Additional oncogenic hits (c-MYC or BCL2 deregulation) will then further promote cell transformation.

Figure 4. Role of EZH2 deregulation in hematological malignancies

EZH2 is deregulated in several hematological malignancies. EZH2 overexpression and gain-of-function mutations are correlated with increased proliferation of tumor cells and poor prognosis in patients with lymphoma. However, EZH2 loss-of function mutations also can be associated with aggressiveness of some hematological malignancies. Therefore, therapeutic molecules targeting EZH2 should not hinder EZH2 tumor-suppressor function. GC B-cell DLBCL: Germinal center B-cell diffuse large B-cell lymphoma; CLL: chronic lymphocytic leukemia; MM: multiple myeloma, MDS: myelodysplastic syndrome; AML: acute myeloid leukemia; ALL: acute lymphocytic leukemia.