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  • Loss of EZH function as a consequence of nonsense or

    2021-10-18

    Loss of EZH2 function as a consequence of nonsense or frameshift mutations has also been detected in a cohort study conducted by Jankowska et al. in chronic myelomonocytic leukemia (CMML) patients, as an early event in cancer development [43]. Although, a recent study in Japan described increased levels of EZH2 in bone marrow mononuclear Moxidectin (BMMNCs) isolated from patients with CML compared with normal individuals and Philadelphia chromosome-negative myeloproliferative neoplasms [44]. Moreover, a research investigating gene expression profile of human CML cells revealed that CML cells and their respective leukemia-initiating cells (LICs) are dependent on EZH2 [45]. Notably, expression of EZH2 is sustained by BCR–ABL1 signaling in CML cells as TKIs (imatinib or dasatinib) diminish EZH2 protein levels [45]. A crucial molecular feature of CML is BCR/ABL fusion, the product of a chromosomal translocation that activates cell signaling pathway components and transcription factors such as STAT5, (PI3K)/AKT, RAS/MAPK/ERK and NF-κB in these malignant cells [44]. The members of STAT family transcription factors include STAT1, 2, 3, 4, 5A, 5B and 6 [46]. It was shown that STAT5A is associated with promoter of EZH2 gene and correlates with an aberrant increase in transcription of EZH2 in Ph-positive leukemia cells, suggesting STAT5A as a positive regulator of EZH2 in leukemia cells [44]. To confirm the requirement of LICs for EZH2, the consequences of EZH2 loss in LICs were assessed in the engineered mouse model of CML [45]. Moxidectin The results showed that inactivation of EZH2 eliminated the functional LICs, impaired initiation and development of leukemia and led to markedly improved survival of mouse [45]. Trithorax (Trx) group proteins have counteracting roles with PcG in setting epigenetic regulation of genes involved in establishment of stem cell state and development [47]. The Trx group member, MLL, maintain HOX gene activity in hematopoietic precursors, partly by H3K4 trimethylation [48]. A high level of HOX gene expression is present in hematopoietic precursors and differentiation of these cells is associated with reduced expression of HOX genes [49]. The most frequent mutation of MLL, is a chromosomal rearrangement which results in a fusion transcript through binding to one of a large spectrum of partner genes, often to AF9 in AML [50]. MLL-fusion AML is characterized with an abnormal differentiation block in myeloid lineage and inappropriate self-renewal capacity in c-Kit/CD117 positive leukemia stem cell subpopulations [51,52]. Studies performed in a murine model have demonstrated that the complex of PRC2, along with MLL-AF9 are responsible for blockade of myeloid differentiation in AML leukemia [53]. The suppression of differentiation is at least partly influenced by HOX genes expression mediated by MLL-AF9, and PcG protein EZH2 regulates C/EBPα and contributes to differentiation block in MLL-fusion leukemia in collaboration with MLL [54]. C/EBPα is a critical factor that controls myeloid differentiation [55]. EZH2 interaction with promoter region of C/EBPα target genes renders suppression of C/EBPα target genes in MA9 cells [54]. Fig. 1 depicts the genetic events resulting to MLL-derived AML transformation. Consistent with this finding, several works reported that genetic depletion of EZH2 promotes primary leukemia cell differentiation and reduces susceptibility to MLL⁄AF9- transformed leukemia in murine models [53,56,57] and a recent work has shown that inhibition of EZH2 in MLL-induced leukemia has treatment advantages by decreasing leukemia initiating cells (LIC) subpopulations via upregulation of p16 [58]. These results reveal that p16 is a real target of EZH2 and suppression of p16 is required to maintain MLL-derived leukemia. Ueda et al. demonstrated the in vivo efficacy of EZH2 inhibition for the treatment of mice with MLL-derived leukemia in which the survival of mice were prolonged [58]. More recently, concurrent inhibition of both EZH2 and EZH1 using an oral selective inhibitor conferred increased survival in MLL-induced leukemia of murine models, further confirming that targeting EZH2 (and EZH1) is a prospective therapeutic approach in MLL-induced leukemias [59]. Targeting the other polycomb group protein, Bmi1, a component of PRC1, that is required for initiating MLL⁄AF9 leukemia, appeared to have no therapeutic advantages [60], suggesting that EZH2 acts as an important therapeutic target among PcG proteins [58]. Moreover, in the previous studies, 3-deazaneplanocin A (DZNep), an inhibitor of EZH2, was reported to have killing effects on leukemic cells [61,62]. However, pharmacological inhibition of Dot1L, the enzyme implicated in di-methylation of histone H3 on K79, the histone mark that bear dysregulated methylation in MLL fusion leukemia [61,62] was shown to be less effective in mouse models of MLL-AF9 leukemia [63]. On the other hand, the results from serial transplantation experiments on murine models highlighted the importance of EZH2 in cancer progression but not essential requirement for MLL-AF9 AML [56]. It was found that genetic loss of EZH2 restricts, but does not terminate, leukemia growth. MLL-AF9 leukemic cells with loss of EZH2, maintain H3K27me mark on many genes, proposing EZH1 as an alternative factor, as previously [11] was shown in ESCs [56]. In contrast, complete loss of PRC2 function by inactivation of EED fully abrogates self-renewal of leukemia [56]. Overall, the authors declared a role for EZH1 in MLL-AF9 leukemia that needs detailed studies in the future [56].