Overexpression of miR-29a and miR-29b is involved in imatinib resistance via abrogated NF1 expression and increased ERK1/2 activation in chronic myeloid leukemia cells.

Breakpoint cluster region::Abelson 1 (BCR::ABL1) tyrosine kinase inhibitors (TKIs), such as imatinib, are used to treat chronic myeloid leukemia (CML), but BCR::ABL1 TKI resistance develops in 20-30% of affected patients, which poses a serious clinical problem. MicroRNAs (miRNAs) have been related to the development and aggravation of CML and BCR::ABL1 TKI resistance; however, the underlying mechanisms remain unknown. In this study, we explored the roles of miRNAs in imatinib resistance as well as the underlying mechanism in imatinib-resistant K562 (K562/IR) cells. Gene amplification was analyzed using array comparative genomic hybridization. Cell survival was confirmed by trypan blue dye staining assay. Expression of protein and miRNA was assessed using western blotting and real-time polymerase chain reaction (PCR). We found that miR-29a, miR-29b, miR-592, miR-595, miR-671, miR-3666, and miR-3907 were upregulated. Real-time PCR confirmed increased expression of miR-29a and miR-29b in K562/IR cells. Additionally, miR-29a and miR-29b mimics reduced imatinib sensitivity in K562 cells. We also found that miR-29a and miR-29b inhibitors partially overcame imatinib resistance in K562/IR cells. Furthermore, miR-29a and miR-29b mimics enhanced extracellular signal-regulated kinase (ERK) 1/2 activity by decreasing neurofibromin 1 (NF1) expression in K562 cells, whereas miR-29a and miR-29b inhibitors reduced ERK1/2 activation by increasing NF1 expression in K562/IR cells. These findings indicated that miR-29a and miR-29b are involved in imatinib resistance by downregulating NF1 expression and activating ERK1/2. Additionally, the miR-29a, miR-29b, and NF1/ERK axis may be potential targets for the treatment of imatinib-resistant CML.