95 9 mg Murine models of AML were

Murine models of AML were used to identify differentially expressed proteins following treatment with the EZH2 inhibitor, DZnep. Sandow and coworkers demonstrated that inhibition of EZH2 induces leukemia 95 9 mg arrest through regulation of cyclin-dependent kinases and increased expression of p53, a crucial tumor suppressor that regulates proliferation and survival [64]. Results of an in vitro study in 2015 has shown that administration of arsenic trioxide (ATO), a chemotherapeutic agent, is able to induce EZH2 expression, which inhibits apoptosis and mediates chemotherapy resistance in AML cell lines [65]. Knockdown of EZH2 enhanced the ATO-induced apoptosis of leukemic cell lines, through downregulation of Wnt/βcatenin activation. The Wnt signaling is an important pathway in cancer biology which is implicated in AML development as well as self-renewal and survival of leukemic cells [65]. EZH2 was found to regulate Wnt/βcatenin signaling by promoting GSK-3β phosphorylation. These findings suggest that EZH2 may serve as a potential therapeutic target for myeloid malignancies, in particular AML. In contrast, a recently published literature suggested that restoring EZH2 protein is a therapeutic approach to overcome therapy resistance in AML [66]. Chemoresistance of AML cell lines and primary cells in a mouse model as well as in vitro was induced when EZH2 protein was suppressed. It was detected that proteasomal degradation of EZH2 which involves interaction with CDK1 and subsequent phosphorylation of EZH2 followed by ubiquitination is implicated in decreased expression of EZH2 and chemoresistance [66]. Treatment with inhibitors of CDK1 or proteasome effectively restored the protein levels of EZH2 and redirected the cells to chemosensitivity [66]. The consequences resulted from these studies is controversial and further research is needed to elucidate the role of EZH2 in chemoresistance of AML cells. Since Myelodysplastic syndromes and myeloproliferative neoplasms can progress to AML [67], and as described above, EZH2 mutations are linked with poor survival in MDS but not with increased transformation to AML; opposing role for PRC2 function in chronic and acute myeloid malignancies is indicated, which is supported by the absence of EZH2 mutations in de novo AML [7]. Heterogeneity of AML associated with different cytogenetics may be linked with EZH2 gene function based on evidences indicating that MLL-rearranged (t (9;22)) leukemias harbor EZH2 hyperactivity; conversely translocation 8;21 may be accompanied by EZH2 loss of function mutations in specific cases [34,56], suggesting new considerations in therapeutic approaches in myeloid malignancies. More research is needed to fully elucidate the in vivo effects of PRC2 overexpression or inactivation in normal and malignant conditions to improve our knowledge of the role of PRC2 proteins in particular EZH2 in myeloid leukaemogenesis.
The correlation of EZH2 in lymphoid leukemia
Targeting EZH2 in leukemia The most common therapeutic strategy to inhibit EZH2 is DZNep, which can affect the cellular EZH2 protein amount. It is a pharmacological approach to decrease EZH2 protein level in cancer cells [104]. DZNep provides depletion of EZH2 through SAH-hydrolase inhibition. Elevation in intracellular concentration of SAH is a negative feedback mechanism leading to PRC2 complex degradation. Therefore, DZNep is not a specific inhibitor of EZH2, since EED and SUZ12 components are also affected by DZNep [105]. Due to the appropriate selective effect of DZNep on cancer cells, it is a suitable therapeutic agent. DZNep is able to arise de-repression of PRC2 target genes and induce apoptosis in brain, breast, colorectal, liver, lung, and prostate cancer cells with no toxicity as normal CD4 + T cells were not sensitive to DZNep [106,107]. Studies have shown that ATL cell lines treated with DZNep also display attenuated proliferation. Treatment of T-ALL cell lines with DZNep showed similar sensitivities, indicating the notion that DZNep toxicity toward lymphoma and leukemia cells is not strictly related to histone modification .[81]. In acute myeloid leukemia, DZNep mediates apoptosis by inhibiting thioredoxin activity, reactivating TXNIP and increasing reactive oxygen species [108]. The multiple action of DZNep, limits its use as a targeted probe to study EZH2 in PRC2 complex [109]. GSK343 is an efficient blocker of EZH2 demonstrated in cellular and enzyme assays [110] which exhibits a high potency and more selectivity against EZH2 much more than its selectivity against other methyltransferases [109]. The other inhibitor of EZH2, GSK126 has been found to be the most potent inhibitor so far. This small-molecule component displays [111] activity against EZH2 by a mechanism other than PRC2 protein degradation [112]. GSK126 demonstrate good inhibitory activity on DLBCL cell lines bearing EZH2 mutation through proliferation arrest and show intensive effects in EZH2-mutant DLBCL bearing mice of xenograft models [111].