Moreover long term treatment of leukemia cells with imatinib

Moreover, long term treatment of leukemia cells with imatinib activates AKT, ERK and STAT5 signaling pathway and induce upregulation of EZH2 protein in patients with CML, Ph + ALL and human eosinophilic leukemia cell line (EOL-1 cells) [142]. So, resistance to tyrosine kinase inhibitor (TKI) imatinib in leukemia cells is mediated by the expression of EZH2 [142] suggesting that in particular conditions anti-epigenetic agents may be a promising approach to improve therapy response in patients receiving tyrosine kinase inhibitors. This group have previously established K562 cells resistant to dasatinib (K562DR) in which both BCR/ABL and STAT5 and not ERK and AKT, were inactivated in contrast to parent K562 cells [143]. K562DR cells were also resistant to growth inhibition by imatinib and increased EZH2 was independent from STAT5 signaling. Notably, miR-217 expression level in K562DR cells were less than those in parental K562 cells. As recent studies report that EZH2 is a direct target of miR-217 in gastric cancer cells [144], this miRNA may exert modulating impacts on expression of EZH2 in K562DR cells [44]. Taken together, data show that BCR/ABL work as an important factor which positively regulates the expression of EZH2 in an STAT5-dependant manner and supports the leukemic cell survival. Thus EZH2 may be a useful target for targeted eradication of CML cells. Table 2 gives a summary of the miRNAs which regulate the expression of EZH2 in leukemia.
Conclusion Cell fate decision is regulated by genetic and epigenetic regulation of gene expression. In particular dynamic chromatin remodeling mediated by polycomb repressive complex controls cellular transcription profile through modification of specific histone residues. PRC2 activity promotes the cellular processes by altering the expression of functional genes that participate in lineage commitment, differentiation and ganciclovir progression. Accumulated evidence demonstrates that dysregulation of EZH2, the catalytic subunit of the complex, as a master regulator of chromatin is frequently observed in a majority of human cancers particularly hematopoietic malignancies. Aberrant expression of EZH2 differentially contributes to the tumor initiation in different types of leukemia. EZH2 acts as a double facet factor either as a tumor suppressor or oncogene in acute and chronic leukemias of myeloid and/or lymphoid origin which suggest the complexity of EZH2-mediated regulation of mammalian gene expression. Several molecules are implicated in the regulation of EZH2. MiRNA-dependent regulation of EZH2 is involved in multiple cancers. Therefore, specific strategies for modulation of EZH2 by manipulating miRNAs regulating the expression and function of EZH2 protein may lead to production of more specific and effective therapeutic agents to achieve a precise therapy. Pointing to the multi-faceted role of EZH2 in different types of leukemia, development of context specific strategy for example by using siRNAs or shRNAs [145] could be considered in future personalized targeted medicine for leukemia. However, to establish the appropriate therapy we should elucidate the true EZH2 dependency of tumor cells by a deeper understanding based on large scale genetic and epigenetic studies.
Introduction Recurrent miscarriage is defined as two or more failed clinical pregnancies, which are verified by ultrasonography or histopathologic examination. Recurrent miscarriage (RM) is one of the most common clinical problems in reproduction, and it affects 2%–5% of childbearing couples. Common established etiology includes advanced maternal ages, uterine anomalies, immune dysregulations, hormonal and metabolic disorders, environmental factors, and cytogenetic abnormalities. However, less than 50% of couples with RM are diagnosed with an exact etiology. Previous studies have revealed that shallow or insufficient extravillous trophoblast (EVT) invasion is implicated in the pathogenesis of RM.4, 5 In recent years, it has been increasingly appreciated that epigenetic factors, such as histone modification and DNA methylation, are involved in pregnancy outcomes through regulating trophoblast functions, which are responsible for the healthy development of the fetus.6, 7, 8, 9