Hyperactivation of Notch pathway can give

Hyperactivation of Notch1 pathway can give rise to transformation into T-ALL in murine models. In more than 50% of acute T-cell lymphoblastic leukemias oncogenic activating mutations of Notch1 have been detected and inactivation of Notch1 signaling impairs leukemia cell proliferation and promotes apoptosis in the T-ALL cells [129]. Qian et al. identified that Notch1 is directly regulated by miR-101 [129]. These data indicate that a critical mechanism underlying miR-101 effects on T-ALL is at least in part through suppression of Notch1. Moreover, in vitro experiments demonstrated that miR-101 is related to chemoresistancy of Jurkat cells to Adriamycin, a chemotherapy agent [129]. Thus, miR-101 can be considered as a potent target for therapy in T-ALL. It is reported that miR26A1 is altered in several cancer types for example Burkitt’s lymphoma and thyroid anaplastic carcinoma operating as a tumor suppressor [130,131]. It was also reported that several signaling pathways, such as p53 and TGF-β signaling, and some tumor-associated genes including SMAD1 [132] and EZH2 [130] are regulated by miR26A1. Apparent effects of high EZH2 expression on adverse prognosis and aggressiveness of B cell leukemias bring forward identifying the miRNAs that potentially mediate regulation of EZH2 and provide novel therapeutic approaches for treatment of B cell leukemia. The expression level of miR26A1 in patients with CLL is lower than that in normal DL-α-Hydroxyglutaric acid disodium salt [133,134]. Indeed, it was shown that two subtypes of CLL, mutated and unmutated subgroups, have different methylation state of miR26A1 promoter. Severe forms of disease with IgV-unmutated gene and poor prognosis represent with significantly higher methylation level as shown in a number of high-throughput studies [133,[135], [136], [137]]. These findings suggest that DNA hypermethylation of miR26A1 leading to gene silencing, appears to be an epigenetic regulating mechanism associated with EZH2 overexpression in pathobiology of CLL disease [137]. Indeed, miR26A1 overexpressing cell lines, display decreased level of EZH2 which result in induction of apoptotic cell death confirming the important role of miR26A1 in tumor suppression in this malignancy. Interestingly, loss of miR-101 is implicated in EZH2 overexpression in aggressive CLLs [138]. Despite the CLL cells, miR-101 is upregulated in chronic phases of individuals with chronic myeloid leukemia [139]. However, in the case of acute myeloid malignancies downregulation of miR-101a was shown in MLL-rearranged AML stem cells and ectopic expression of this miRNA disrupted LSC functions through altering epigenetic profile and suppressing survival signaling which leads to leukemia stem cell apoptosis. Thereby induction of miR-101a overexpression may develop a new strategy to eradicate LSCs with drug-resistance properties [140]. Whereas miR-26a function as a tumor suppressor miRNA in AML, experimental data showed that EZH2 is not a direct target of miR-26a in acute myeloid leukemia cells [141]. In myeloid leukemia cells, EZH2 is transcriptionally regulated by c-Myc, causing cancer by enforcing E2F1 activity and participating in the increased EZH2 level in leukemia cells [141]. Chemotherapy resistance and relapse are probably the most problematic issue in the treatment process of patients with acute myeloid leukemia [28]. More recently, Göllner et al. reported that loss of EZH2 and reduction of histone methyltransferase activity with subsequently decreased level of H3K27 trimethylation contribute to chemoresistancy in AML patients with del(7)/del(7q) [28]. Noticeably, reducing the protein levels of EZH2 via treatment with H3K27 methyltransferase inhibitors or lentiviral knockdown, revealed chemoresistant properties in Normal Karyotype (NK)-AML blasts and cell lines in vitro and in a xenograft mouse model [28]. These results suggest that EZH2 protein deposition for example via proteasome inhibitors may provide a means for restoration of EZH2 function and thereby may be hopeful to overcome drug-resistance in AML.