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

作　　者：Mengping Xi Shanshan Guo Caicike Bayin Lijun peng Florent Chuffart Ekaterina Bourova-Flin Sophie Rousseaux Saadi Khochbin Jian-Qing Mi Jin Wang 

机构地区：[1]Shanghai Institute of Hematology,State Key Laboratory of Medical Genomics,National Research Center for Translational Medicine at Shanghai,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [2]Pôle de Recherches Sino-Français en Science du Vivant et Génomique,Shanghai 200025,China [3]CNRS UMR 5309/INSERM U1209/UniversitéGrenoble Alpes/Institute for Advanced Biosciences,38706 La Tronche,France

出　　处：《Frontiers of Medicine》2022年第3期442-458,共17页医学前沿（英文版）

基　　金：This study was fiunded by the Shanghai Science and Technology Commitee(No.21430711800),National Natural Science Founda-tion of China(Nos.81670147,81570178,and Antrag M-0377);Gaofeng Clinical Medicine Grant Support of Shanghai Municipal Education No.20172002);Shanghai Municipal Education Com-mission-Major Project for Scientifc 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 fom the"Universite Grenoble Alpes"ANR-15-IDEX-02 LIFE and SYMER programs,as well as the INSERMTTMO/Aviesan MIC 2021 program(roject ECTOCAN).

摘　　要：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.

关 键 词：T-cell acute lymphoblastic leukemia HDAC inhibitor CHIDAMIDE NOTCH1 MYC UBIQUITINATION 

分 类 号：R733.7[医药卫生—肿瘤]