Elevated levels of microRNA miR-155 represent a candidate pathogenic factor in chronic B-lymphocytic leukemia (B-CLL). In this study, we present evidence that MYB (v-myb myeloblastosis viral oncogene homolog) is overexpressed in a subset of B-CLL patients. MYB physically associates with the promoter of miR-155 host gene (MIR155HG, also known as BIC, B-cell integration cluster) and stimulates its transcription. This coincides with the hypermethylated histone H3K4 residue and spread hyperacetylation of H3K9 at MIR155HG promoter. Our data provide evidence of oncogenic activities of MYB in B-CLL that include its stimulatory role in MIR155HG transcription.

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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.