miR-495-3p Sensitizes BCR::ABL1 Expressing Leukemic cells to Tyrosine Kinase Inhibitors by Targeting Multidrug Resistance 1 Gene including in T315I Mutated cells

Abstract

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 of ATP-binding cassette (ABC) transporters. Increasing evidence suggests an involvement of the microRNA miR-495-3p in cancer-associated chemo-resistance 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 non-dividing cells (G0/G1) and resistance to Imatinib. Conversely, our data showed that miR-495-3p overexpression hindered leukemic cell growth and TKI resistance even in Imatinib-resistant T315I-mutant cells as well as drug efflux activity through MDR1 regulation. To further investigate the role of miR-495-3p in CML patients, we found that predicted miR-495-3p targets were upregulated in patients in blast crisis involved in protein phosphorylation and associated with the worst prognosis. Taken together, our results demonstrate that down-regulation of miR-495-3p expression is important in the malignant phenotype of CML and TKI resistance mechanisms, which could be a useful biomarker and a potential therapeutic target to eradicate CML. MeSH termsO_LIATP Binding Cassette Transporter, Subfamily B C_LIO_LIATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects C_LIO_LIATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism* C_LIO_LIBlast Crisis / pathology C_LIO_LICell Line, Tumor C_LIO_LICell Proliferation / drug effects* C_LIO_LICell Survival / drug effects C_LIO_LIDrug Resistance C_LIO_LIGenes, MDR C_LIO_LIImatinib Mesylate C_LIO_LILeukemia, Myelogenous, Chronic, BCR-ABL Positive C_LIO_LIMicroRNAs / genetics C_LIO_LIMicroRNAs / physiology* C_LI HIGHLIGHTSO_LImiR-495-3p inhibits leukemic cell growth and is downregulated in BCR::ABL1 expressing cell lines C_LIO_LImiR-495-3p modulates response to TKI treatment including in UT7 cells expressing T315I C_LIO_LIOverexpression of miR-495-3p leads to a decrease of MDR1 and drug efflux activity C_LIO_LIBioinformatics analyses reveal that MiR-495-3p target genes are upregulated in blast crisis C_LI