Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

Abstract

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.

Keywords

T-cell acute lymphoblastic leukemia / HDAC inhibitor / chidamide / NOTCH1 / MYC / ubiquitination

References

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Acknowledgements

This study was funded by the Shanghai Science and Technology Committee (No. 21430711800), National Natural Science Foundation of China (Nos. 81670147, 81570178, and Antrag M-0377), Gaofeng Clinical Medicine Grant Support of Shanghai Municipal Education (No. 20172002), Shanghai Municipal Education Commission-Major Project for Scientific Research and Innovation Plan of Natural Science (No. 2021-01-07-00-02-E00091). SK laboratory is supported by “Fondation ARC” grant (PGA1RF20190208471) and the ANR EpiSperm 4 program. Additional supports were from the “Université Grenoble Alpes” ANR-15-IDEX-02 LIFE and SYMER programs, as well as the INSERM/ITMO/Aviesan MIC 2021 program (project ECTOCAN).

Compliance with ethics guidelines

Mengping Xi, Shanshan Guo, Caicike Bayin, Lijun peng, Florent Chuffart, Ekaterina Bourova-Flin, Sophie Rousseaux, Saadi Khochbin, Jian-Qing Mi, and Jin Wang declare that they have no conflict of interest. All procedures performed in studies involving human samples were approved by the ethics committee at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine and Shanghai Blood Center, and in accordance with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. All patients gave written informed consent prior to bone marrow sample collection for the use of biomaterials and clinical data for scientific purposes.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-021-0877-y and is accessible for authorized users.

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