Chronic myeloid leukemia (CML) is a clonal hematopoietic malignancy driven by the BCR-ABL1 fusion oncoprotein. The development of tyrosine kinase inhibitors (TKIs) has deeply increased long-term survival of CML patients. Nonetheless, one patient out of four will switch TKI off owing either to drug intolerance or resistance partly due to amplification or mutations of BCR-ABL1 oncogene and alteration in ATP-binding cassette (ABC) transporters. Increasing evidence suggests the involvement of the microRNA miR-495-3p in cancer-associated chemoresistance through multidrug resistance 1 (MDR1) gene, which encodes an ATP-dependent efflux pump. Our study aimed at investigating the potential role of miR-495-3p in CML TKI chemo-sensitivity and determining the underlying molecular circuitry involved. We first observed that miR-495-3p expression was lower in BCR-ABL1-expressing cellular models in vitro. Notably, loss-of-function experiments showed increased proliferation associated with a decreased number of nondividing cells (G0/G1) and resistance to Imatinib. Conversely, our data showed that miR-495-3p overexpression hindered leukemic cell growth and TKI resistance in Imatinib-resistant T315I-mutant cells, as well as drug efflux activity through MDR1 regulation. Further investigating the role of miR-495-3p in CML patients, we found that predicted miR-495-3p targets were upregulated in patients in blast crisis that were involved in protein phosphorylation and associated with the worst prognosis. Taken together, our results demonstrate that downregulation of miR-495-3p expression is important in the malignant phenotype of CML and TKI resistance mechanisms and could be a useful biomarker and a potential therapeutic target to eradicate CML.
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