摘要Chronic myeloid leukemia(CML)is a hematopoietic malignancy driven by the fusion gene BCR::ABL1.Drug resistance to tyrosine kinase inhibitors(TKIs)due to BCR::ABL1 mutation and residual leukemia stem cells(LSCs)remain major challenges for CML treatment.Here,we revealed the requirement of vitamin D receptor(VDR)in the progression of CML,in which VDR was upregulated by BCR::ABL1,accounting for its high expression.Interestingly,VDR knockdown inhibited the CML cell proliferation driven by BCR::ABL1,regardless of its mutations with resistance to TKIs.Mechanistically,VDR transcriptionally regulated DDIT4 expression,and the inhibition of DDIT4 triggered DNA damage-induced senescence via p53 signaling activation in CML cells.Furthermore,VDR deficiency was sufficient to not only ameliorate the disease burden and progression in primary CML mice but also reduce the self-renewal of CML-LSCs.Together,our study demonstrated that targeting VDR is a promising strategy to overcome TKI resistance and eradicate LSCs in CML.