title: ChREBP promotes the differentiation of leukemia-initiating cells to inhibit leukemogenesis through the TXNIP/RUNX1 pathways.
abstract: Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the maintenance of stemness in LICs, although the detailed mechanisms are poorly understood. Herein, we provide intriguing evidence showing that a glucose-responsive transcription factor, carbohydrate responsive element binding protein (ChREBP), served as a tumor suppressor rather than an oncogene, as previously described, to inhibit the development of acute myeloid leukemia by promoting the differentiation of LICs. Using an MLL-AF9-induced murine leukemia model, we demonstrated that the deletion of ChREBP resulted in the blockage of the differentiation of LICs and significantly reduced survival in ChREBP-null leukemic mice. However, ChREBP was not required for the normal repopulation abilities of hematopoietic stem cells. ChREBP promoted leukemia cell differentiation through the direct inhibition of RUNX1 or the transactivation of TXNIP to downregulate the RUNX1 level and ROS generation. Moreover, knockdown of ChREBP in human leukemia THP1 cells led to markedly enhanced proliferation and decreased differentiation upon PMA treatment. Collectively, we unraveled an unexpected role of ChREBP in leukemogenesis, which may provide valuable clues for developing novel metabolic strategies for leukemia treatment.
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Gu
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Chiqi
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Minle
authors.initials: M
authors.lastname: Li
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Fangzhen
authors.initials: F
authors.lastname: Xia
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiaoye
authors.initials: X
authors.lastname: Liu
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Tong
authors.affiliation: Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Wang
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Junke
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D050676:Core Binding Factor Alpha 2 Subunit; C116385:MLXIPL protein, human; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; C493728:RUNX1 protein, human; C493726:Runx1 protein, mouse; C486715:TXNIP protein, human; D014157:Transcription Factors; C445672:Txnip protein, mouse; D013879:Thioredoxins
keywords: ChREBP; TXNIP; differentiation; leukemia initiating cells; metabolism