De-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses CML cell apoptosis and contributes to Imatinib resistance.

plays an important role in the transformation of hematopoietic cells by BCR-ABL. However, the downstream target genes activated by in chronic myeloid leukemia (CML) cells remain largely unclear. Here, we investigated the mechanistic functional relationship between microRNA and CML cell apoptosis. METHODS:The expression of USP15, Caspase-6, duanyu18135A-regulated miR-202-5p and was detected by qRT-PCR and Western blotting in CML cell lines and PBMCs of CML patients. Cell apoptosis was evaluated by flow cytometry. Both gain- and loss-of-function experiments were used to investigate the roles of USP15, miR-202-5p and duanyu18135A in CML. Luciferase reporter assay detected the effect of miR-202-5p on USP15 expression. Xenograft animal model was used to test the effect of anti-miR-202-5p and pimozide on K562 cell xenograft growth. RESULTS:USP15 expression was significantly downregulated in CML cell lines and PBMCs of CML patients. Depletion of USP15 increased, whereas overexpression of USP15 reduced the resistance of CML cells to Imatinib. Further, decreased deubiquitinating activity of USP15 by USP15 downregulation led to reduced caspase-6 level, thus attenuating CML cell apoptosis. Mechanistically, miR-202-5p was upregulated in K562G cells and negatively regulated USP15 expression by directly targeting USP15 3'-UTR. Correspondingly, upregulation of miR-202-5p enhanced the resistance of CML cells to Imatinib by inhibiting cell apoptosis. Importantly, duanyu18135A was upregulated in CML cells and directly activated miR-202-5p transcription by binding to the pre-miR-202 promoter. Pimozide induced CML cell apoptosis and significantly reduced K562 cell xenograft growth in vivo by blocking regulatory axis. CONCLUSIONS:we provide the first evidence that de-regulated duanyu18135A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses the apoptosis of CML cells, targeting this pathway might be a promising therapeutic approach for the treatment of CML.

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