EZH2 in Myeloid Malignancies

Abstract

Our understanding of the significance of epigenetic dysregulation in the pathogenesis of myeloid malignancies has greatly advanced in the past decade. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic core component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for gene silencing through trimethylation of H3K27. EZH2 dysregulation is highly tumorigenic and has been observed in various cancers, with EZH2 acting as an oncogene or a tumor-suppressor depending on cellular context. While loss-of-function mutations of EZH2 frequently affect patients with myelodysplastic/myeloproliferative neoplasms, myelodysplastic syndrome and myelofibrosis, cases of chronic myeloid leukemia (CML) seem to be largely characterized by EZH2 overexpression. A variety of other factors frequently aberrant in myeloid leukemia can affect PRC2 function and disease pathogenesis, including Additional Sex Combs Like 1 (ASXL1) and splicing gene mutations. As the genetic background of myeloid malignancies is largely heterogeneous, it is not surprising that EZH2 mutations act in conjunction with other aberrations. Since EZH2 mutations are considered to be early events in disease pathogenesis, they are of therapeutic interest to researchers, though targeting of EZH2 loss-of-function does present unique challenges. Preliminary research indicates that combined tyrosine kinase inhibitor (TKI) and EZH2 inhibitor therapy may provide a strategy to eliminate the residual disease burden in CML to allow patients to remain in treatment-free remission.

Keywords: ASXL1; CML; EZH2; MDS; MPN; PRC2; mutations; myeloid malignancies.

Figure 1

PRC2 and its function in transcriptional regulation. The PRC2 facilitates gene silencing through methylation of H3 lysine 27 and is composed of the core components Enhancer of Zeste Homolog 2 (EZH2), Embryonic Ectoderm Development (EED), Suppressor of Zeste 12 (SUZ12) and Retinoblastoma-binding Protein (RBBP7/4). Other non-essential regulatory proteins, thought to have modulatory and enhancing effects on PRC2 function, include Adipocyte Enhancer-binding Protein 2 (AEBP2), Polycomb-like Proteins (PCLs) and Jumonji and AT-rich Interaction Domain Containing 2 (JARID2) [4,6]. The polycomb complex PRC1, ubiquitinates H2A lysine 119 (H2AK119) and can act downstream of PRC2 to induce gene repression, by binding of trimethylated H3 lysine 27 (H3K27me3) via its Chromobox (CBX) component. Other components include Polycomb Group RING Finger Protein 4 (BMI1), Ring Finger Protein 1 (RING1) and Polyhomeotic Homolog 1 (PHC1) [5]. EZH2 physically interacts with Additional Sex Combs Like 1 (ASXL1) for PRC2 recruitment to target genes [10] and DNA Methyltransferases (DNMTs) to regulate DNA methylation [11]. Demethylation of H3K27 is facilitated through Lysine Demethylase 6A (KDM6A/UTX) and Lysine Demethylase 6B (KDM6B/JMJD3) [12]. me: methylation; ub: ubiquitination; ON/OFF: transcriptional activation/repression of target genes such as Homeobox (HOX) genes.

Figure 2

Clonal evolution of myeloid malignancies with loss-of-function mutations of EZH2. Loss-of-function mutations of Enhancer of Zeste Homolog 2 (EZH2) are thought to be early events in clonal evolution of myeloid malignancies. Studies have shown that mutations of EZH2 can precede the acquisition of mutations of other epigenetic regulators such as Ten-Eleven Translocation Methylcytosine Dioxygenase 2 (TET2). Signaling gene mutations usually occur later in disease evolution. Additional Sex Combs Like 1 (ASXL1) mutations have been shown to precede the acquisition of EZH2 mutations [20,60,74]. Unlike EZH2 mutations, ASXL1 mutations have been shown to be involved in age-related clonal hematopoiesis (ARCH) [75,76,77], suggesting loss-of-function EZH2 mutations are highly oncogenic and frequently involved in leukemia initiation. HSC: Hematopoietic stem cell; JAK2: Janus Kinase 2; KRAS: Kirsten Rat Sarcoma Viral Oncogene Homolog; SETBP1: SET-binding Protein 1.