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作者单位

Key Lab of Chemical Biology(MOE)，School of Pharmaceutical Sciences，Cheeloo College of Medicine，Shandong University，Jinan 250012，China；NMPA Key Laboratory for Technology Research and Evaluation of Drug Products，School of Pharmaceutical Sciences，Cheeloo College of Medicine，Shandong University，Jinan 250012，China；Department of Pharmacology，School of Pharmaceutical Sciences，Cheeloo College of Medicine，Shandong University，Jinan 250012，China；School of Pharmaceutical Sciences&Institute of Materia Medica，Shandong First Medical University&Shandong Academy of Medical Sciences，Jinan 250012，China；Department of Hematology，Heze Municipal Hospital，Heze 274031，China；Key Lab of Chemical Biology(MOE)，School of Pharmaceutical Sciences，Cheeloo College of Medicine，Shandong University，Jinan 250012，China；NMPA Key Laboratory for Technology Research and Evaluation of Drug Products，School of Pharmaceutical Sciences，Cheeloo College of Medicine，Shandong University，Jinan 250012，China

刊名

分子细胞生物学报(英文版)

年份

2023

卷号

第10期

页码

65-76

ISSN

1673-520X

关键词

vitamin D receptor senescence chronic myeloid leukemia DDIT4

摘要

Chronic myeloid leukemiais a hematopoietic malignancy driven by the fusion gene BCR::ABL1.Drug resistance to tyrosine kinase inhibitorsdue to BCR::ABL1 mutation and residual leukemia stem cellsremain major challenges for CML treatment.Here,we revealed the requirement of vitamin D receptorin 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 mutat...更多

Chronic myeloid leukemiais a hematopoietic malignancy driven by the fusion gene BCR::ABL1.Drug resistance to tyrosine kinase inhibitorsdue to BCR::ABL1 mutation and residual leukemia stem cellsremain major challenges for CML treatment.Here,we revealed the requirement of vitamin D receptorin 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.收起

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