title: CD244 maintains the proliferation ability of leukemia initiating cells through SHP-2/p27kip1signaling.
abstract: Targeting leukemia initiating cells is considered to be an effective way to cure leukemia, for which it is critical to identify novel therapeutic targets. Herein, we demonstrate that CD244, which was initially reported as a key regulator for natural killer cells, is highly expressed on both mouse and human leukemia initiating cells. Upon CD244 knockdown, human leukemia cell lines and primary leukemia cells have markedly impaired proliferation abilities bothin vitroandin vivoInterestingly, the repopulation ability of both mouse and human hematopoietic stem cells is not impaired upon CD244 knockdown. Using an MLL-AF9-induced murine acute myeloid leukemia model, we show that leukemogenesis is dramatically delayed upon CD244 deletion, together with remarkably reduced Mac1+/c-Kit+leukemia cells (enriched for leukemia initiating cells). Mechanistically, we reveal that CD244 is associated with c-Kit and p27 except for SHP-2 as previously reported. CD244 co-operates with c-Kit to activate SHP-2 signaling to dephosphorylate p27 and maintain its stability to promote leukemia development. Collectively, we provide intriguing evidence that the surface immune molecule CD244 plays an important role in the maintenance of stemness of leukemia initiating cells, but not in hematopoietic stem cells. CD244 may represent a novel therapeutic target for the treatment of acute myeloid leukemia.
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, 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, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Chiqi
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Hematology, The 1 People's Hospital, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Binzhou Medical University, Taishan Scholar Immunology Program, Yantai, China.
authors.forename: Jingjing
authors.initials: J
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, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Hematology, The 1 People's Hospital, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Bai
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Tongji Hospital of Tongji University School of Medicine, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Fang
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Hematology, The 1 People's Hospital, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Chun
authors.initials: C
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, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Weng
authors.affiliation: Departments of Physiology and Developmental Biology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Cheng Cheng
authors.initials: CC
authors.lastname: Zhang
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, China chengq@shsmu.edu.cn zhengjunke@shsmu.edu.cn lab7182@tongji.edu.cn.
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
authors.affiliation: Department of Hematology, Tongji Hospital of Tongji University School of Medicine, Shanghai, China chengq@shsmu.edu.cn zhengjunke@shsmu.edu.cn lab7182@tongji.edu.cn.
authors.forename: Aibing
authors.initials: A
authors.lastname: Liang
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, China chengq@shsmu.edu.cn zhengjunke@shsmu.edu.cn lab7182@tongji.edu.cn.
authors.forename: Junke
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000818:Animals; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D016130:Immunophenotyping; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D055550:Protein Stability; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D015398:Signal Transduction; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C084093:CD244 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11