miR-139-5p controls translation in myeloid leukemia through EIF4G2.

摘要: MicroRNAs (miRNAs) are crucial components of homeostatic and developmental gene regulation. In turn, dysregulation miRNA expression is a common feature different types cancer, which can be harnessed therapeutically. Here we identify miR-139-5p suppression across several cytogenetically defined acute myeloid leukemia (AML) subgroups. The promoter mir-139 was transcriptionally silenced could reactivated by histone deacetylase inhibitors in dose-dependent manner. Restoration cell lines representing the major AML subgroups (t[8;21], inv[16], mixed lineage leukemia-rearranged complex karyotype AML) caused cycle arrest apoptosis vitro xenograft mouse models vivo. During normal hematopoiesis, exclusively expressed terminally differentiated neutrophils macrophages. Ectopic repressed proliferation CD34+-hematopoietic stem progenitor cells perturbed myelomonocytic differentiation. Mechanistically, exerts its effects repressing translation initiation factor EIF4G2, thereby reducing overall protein synthesis while specifically inducing inhibitor p27Kip1. Knockdown EIF4G2 recapitulated mir-139, whereas restoring rescued phenotype. Moreover, elevated associated with favorable outcome cohort 165 pediatric patients AML. Thus, acts as global tumor suppressor-miR controlling translation. As dependent on high rates constitutes novel path for treatment