期刊
FRONTIERS OF MEDICINE
卷 16, 期 3, 页码 442-458出版社
SPRINGER
DOI: 10.1007/s11684-021-0877-y
关键词
T-cell acute lymphoblastic leukemia; HDAC inhibitor; chidamide; NOTCH1; MYC; ubiquitination
资金
- Shanghai Science and Technology Committee [21430711800]
- National Natural Science Foundation of China [81670147, 81570178, Antrag M-0377]
- Gaofeng Clinical Medicine Grant Support of Shanghai Municipal Education [20172002]
- Shanghai Municipal Education Commission-Major Project for Scientific Research and Innovation Plan of Natural Science [2021-01-07-00-02-E00091]
- Fondation ARC grant [PGA1RF20190208471]
- ANR EpiSperm 4 program
- Universite Grenoble Alpes [ANR-15-IDEX-02 LIFE]
- SYMER programs
- INSERM/ITMO/Aviesan MIC 2021 program (project ECTOCAN)
This study found that the HDAC inhibitor chidamide has an anti-tumor effect on T-ALL cells, particularly by inhibiting the NOTCH1-MYC signaling axis. Clinical trial results support that chidamide treatment reduces minimal residual disease in patients and is well tolerated.
T-cell acute lymphoblastic leukemia (T-ALL) is one of the most dangerous hematological malignancies, with high tumor heterogeneity and poor prognosis. More than 60% of T-ALL patients carry NOTCH1 gene mutations, leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways. We found that chidamide, an HDAC inhibitor, exerts an antitumor effect on T-ALL cell lines and primary cells including an anti-NOTCH1 activity. In particular, chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1 (NICD1) as well as MYC, partly through their ubiquitination and degradation by the proteasome pathway. We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease (MRD) in patients and is well tolerated. Our results highlight the effectiveness and safety of chidamide in the treatment of T-ALL patients, including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients.
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