BCR-ABL1 mediated miR-150 downregulation through MYC contributed to myeloid differentiation block and drug resistance in chronic myeloid leukemia

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Abstract
The fusion oncoprotein BCR-ABL1 exhibits aberrant tyrosine kinase activity and has been proposed to deregulate signaling networks involving both transcription factors and non-coding microRNAs that result in chronic myeloid leukemia. Previously, microRNA expression profiling showed deregulated expression of miR-150 and miR-155 in chronic myeloid leukemia. In this study, we placed these findings into the broader context of the MYC/miR-150/MYB/miR-155/PU.1 oncogenic network. We propose that upregulated MYC and miR-155 in CD34+ leukemic stem and progenitor cells in concert with BCR-ABL1 impair the molecular mechanisms of myeloid differentiation associated with low miR-150 and PU.1 levels. We revealed that MYC directly occupied the -11.7 kb and -0.35 kb regulatory regions in the MIR150 gene. MYC occupancy was markedly increased through BCR-ABL1 activity, causing inhibition of MIR150 gene expression in chronic myeloid leukemia CD34+ and CD34- cells. Furthermore, we found an association between reduced miR-150 levels in chronic myeloid leukemia blast cells and their resistance to tyrosine kinase inhibitors. Although tyrosine kinase inhibitors successfully disrupted BCR-ABL1 kinase activity in proliferating chronic myeloid leukemia cells, this treatment inefficiently targeted quiescent leukemic stem cells. The study presents new evidence regarding the MYC/miR-150/MYB/miR-155/PU.1 leukemic network established by aberrant BCR-ABL1 activity. The key connecting nodes of this network may serve as potential druggable targets to overcome resistance of chronic myeloid leukemia stem and progenitor cells.

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