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

ABSTRACTChronic 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 ofBCR::ABL1oncogene and alteration of ATP-binding cassette (ABC) transporters. Increasing evidence suggests an involvement of the microRNA miR-495-3p in cancer-associated chemo-resistance throughmultidrug 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 thatmiR-495-3pexpression was lower in BCR::ABL1 expressing cellular modelsin 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 thatmiR-495-3poverexpression hindered leukemic cell growth and TKI resistance even in Imatinib-resistant T315I-mutant cells as well as drug efflux activity throughMDR1regulation. 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 ofmiR-495-3pexpression 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 termsATP Binding Cassette Transporter, Subfamily BATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effectsATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*Blast Crisis / pathologyCell Line, TumorCell Proliferation / drug effects*Cell Survival / drug effectsDrug ResistanceGenes, MDRImatinib MesylateLeukemia, Myelogenous, Chronic, BCR-ABL PositiveMicroRNAs / geneticsMicroRNAs / physiology*HIGHLIGHTSmiR-495-3p inhibits leukemic cell growth and is downregulated in BCR::ABL1 expressing cell linesmiR-495-3p modulates response to TKI treatment including in UT7 cells expressing T315IOverexpression of miR-495-3p leads to a decrease ofMDR1and drug efflux activityBioinformatics analyses reveal that MiR-495-3p target genes are upregulated in blast crisis