The Functions Of MLL Protein In MiRNA-Mediated Gene Silencing

As an important gene expression regulatory mechanism,mi RNA expression,processing and functional activity are tightly controlled,and the dysregulated expression and processing of cancer-related mi RNAs has been demonstrated to play a crucial role in oncogenesis.However,how the abnormalities of mi RNAs’function contributed to cancer is less understood.Here,we uncovered an unexpected role of mixed-lineage leukemia（MLL）protein,a critical epigenetic factor whose disruption leads to leukemogenesis,in the regulation of mi RNAs’s function.We revealed that the MLL^C180 subunit alone could colocalize with mi RNA-induced silencing complex（mi RISC）components in cytoplasmic processing bodies（P-bodies）,where mi RNA-mediated gene silencing took place.Specifically,MLL was required for mi RNA-mediated m RNA translational repression,but not for m RNA cleavage.Mechanistically,MLL was required for recruiting mi RNA to the mi RISC and P-body core,partly through its binding partner RAN.Furthermore,dysregulation of the mi RNA repression function in MLL leukemic cells due to the lower expression of MLL^C180,was essential for high-level expression of MYC,ensuring the survival of MLL leukemic cells.Moreover,our work revealed that IRAK1/4 inhibitor can improve the efficacy of BET inhibitor in MLL leukemias through restoring the protein level of MLL and the MYC-suppressing function of let-7a,thus proposed a novel rationale of synergistically targeting MYC with IRAKis and BETis for the therapy of MLL leukemias.Taken together,our investigation uncovered a novel function of MLL in mi RNA-mediated gene silencing,and demonstrating a functional link between mi RNA and MLL-rearranged leukemia.