首页|Loss of the vitamin D receptor triggers senescence in chronic myeloid leukemia via DDIT4-mediated DNA damage

Loss of the vitamin D receptor triggers senescence in chronic myeloid leukemia via DDIT4-mediated DNA damage

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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.

vitamin D receptorsenescencechronic myeloid leukemiaDDIT4

Yan Xu、Wentao Qi、Chengzu Zheng、Yuan Li、Zhiyuan Lu、Jianmin Guan、Chunhua Lu、Baobing Zhao

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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

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National Natural Science Foundation of ChinaTaishan Scholars Programprogram for Multidisciplinary Research and Innovation Team of Young Scholars of Shandong Universitykey Program of the Natural Science Foundation of Shandong Provinceprogram for Innovative Research Team at the University of Ministry of Education of ChinaFoundation for Innovative Research Groups of State Key Laboratory of Microbial Technology

81874294TSQN2018120152020QNQT007ZR2022LSW027IRT_17R68WZCX2021-03

2023

10.1093/jmcb/mjad066

分子细胞生物学报(英文版)
中国科学院上海生命科学研究院,生物化学与细胞生物学研究所,中国细胞生物学学会

分子细胞生物学报(英文版)

CSTPCDCSCD
影响因子：0.595
ISSN：1673-520X
年,卷(期)：2023.(10)
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