Exosomal circ_0058493 promotes imatinib resistance via miR-548b-3p/U2SURP axis in CML cells.

The prognosis of CML is affected not only by BCR::ABL1-independent resistance but also by BCR::ABL1-dependent resistance, particularly kinase mutations, both of which cause severe harm and have attracted worldwide attention. Circular RNAs (circRNA) have been assessed as potent regulators of tumor progression and drug resistance by manipulating the expression of target genes in cells and intercellular transmission via exosomes. In our previously study, we screened and identified a novel circRNA, circ_0058493, which presented significant negative relevance with imatinib resistance in CML. However, the underlying mechanism remains obscure. In this study, we found that circ_0058493 could be transmitted from imatinib-resistant cells to sensitive cells and induce sensitive cells to develop imatinib resistance. More critically, we showed that circ_0058493 competitively binds with miR-548b-3p, upregulating its target gene U2SURP expression and affecting the imatinib sensitivity of CML cells. Moreover, U2SURP knockdown suppressed the expression of p-ERK, a crucial protein in Ras/MAPK cancerous signaling pathway. Compared with imatinib optimal responders, the level of miR-548b-3p significantly decreased in PBMCs from patients who failed in imatinib treatment. The analysis of clinical database revealed that elevated U2SURP in HSCs was correlated with the occurrence of CML. In conclusion, our data suggested that targeting circ_0058493/miR-548b-3p/U2SURP axis and exosomal circ_0058493 is a potential therapeutic strategy for improving imatinib efficacy in CML.