LncRNA is associated with the BCR::ABL1 kinase independent mechanism of tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia patients.

BACKGROUND

It is difficult for chronic myeloid leukemia (CML) patients with BCR::ABL1 independent drug resistance to achieve optimal efficacy. The aim of this study is to investigate the BCR::ABL1 kinase independent mechanism of tyrosine kinase inhibitor (TKI) resistance in CML patients to develop targeted therapeutic strategy.

METHODS

Herein, we analyzed the long non-coding RNA (lncRNA) and messenger RNA (mRNA) expression profiles of patients who achieved sustained deep molecular response (DMR) after TKI treatment and patients with non-DMR using RNA-seqencing. Furthermore, the differentially expressed lncRNAs and mRNAs were identified. The expression of chosen lncRNA was validated in an expanded cohort, and bioinformatics analysis was performed to analyze the function of selected mRNA.

RESULTS

LncRNA data analysis indicated the diversity lncRNA profiles among healthy individuals, CML patients with non-DMR, and CML patients with DMR. Differential expression analysis and Veen plot of up-regulated lncRNAs in patients with non-DMR (compared with healthy individuals) and down-regulated lncRNAs in patients with DMR (compared to patients with non-DMR) revealed that lncRNA overexpression might be related to BCR::ABL1 independent TKI resistance of CML patients. The expression of was then verified in an expanded cohort, suggesting that, compared with control group, there was no statistical difference of expression in DMR group, whereas, was up-regulated in non-DMR group. Moreover, the mRNA data analysis of RNA-sequencing was performed. We considered genes that up-regulated in non-DMR group (compared with control group), down-regulated in DMR group (compared with non-DMR group), showed no statistical difference between control and DMR group as the potential genes that associated with TKI resistance of CML patients. A total of 55 corresponding mRNAs were obtained including , a target gene of . Further bioinformatics analysis showed that the major interacted genes of were enriched in several resistance-associated pathways including interleukin -17 signaling pathway and cyclic adenosine monophosphate signaling pathway.

CONCLUSIONS

In conclusion, this work indicates that might be involved in BCR::ABL1 independent TKI resistance of CML patients through targeting , providing a novel target for intervention treatment of CML patients with BCR::ABL1 independent TKI resistance.