title: CD274 promotes cell cycle entry of leukemia-initiating cells through JNK/Cyclin D2 signaling.
abstract: CD274 (programmed death ligand 1, also known as B7H1) is expressed in both solid tumors and hematologic malignancies and is of critical importance for the escape of tumor cells from immune surveillance by inhibiting T cell function via its receptor, programmed death 1 (PD-1). Increasing evidence indicates that functional monoclonal antibodies of CD274 may potently enhance the antitumor effect in many cancers. However, the role of CD274 in leukemia-initiating cells (LICs) remains largely unknown.
  
  
  
  We established an MLL-AF9-induced acute myeloid leukemia (AML) model with wild-type (WT) and CD274-null mice to elucidate the role of CD274 in the cell fates of LICs, including self-renewal, differentiation, cell cycle, and apoptosis. RNA sequencing was performed to reveal the potential downstream targets, the results of which were further validated both in vitro and in vivo.
  
  
  
  In silico analysis indicated that CD274 level was inversely correlated with the overall survival of AML patients. In Mac-1+/c-Kit+mouse LICs, CD274 was expressed at a much higher level than in the normal hematopoietic stem cells (HSCs). The survival of the mice with CD274-null leukemia cells was dramatically extended during the serial transplantation compared with that of their WT counterparts. CD274 deletion led to a significant decrease in LIC frequency and arrest in the G1 phase of the cell cycle. Interestingly, CD274 is not required for the maintenance of HSC pool as shown in our previous study. Mechanistically, we demonstrated that the levels of both phospho-JNK and Cyclin D2 were strikingly downregulated in CD274-null LICs. The overexpression of Cyclin D2 fully rescued the loss of function of CD274. Moreover, CD274 was directly associated with JNK and enhanced the downstream signaling to increase the Cyclin D2 level, promoting leukemia development.
  
  
  
  The surface immune molecule CD274 plays a critical role in the proliferation of LICs. The CD274/JNK/Cyclin D2 pathway promotes the cell cycle entry of LICs, which may serve as a novel therapeutic target for the treatment of leukemia.
authors.affiliation: Department of Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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: Xia
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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 Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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: Department of Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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: Department of Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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 Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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: Hao
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Hematology, Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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: Xiaocui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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: Wei
authors.initials: W
authors.lastname: Weng
authors.affiliation: Departments of Physiology and Developmental Biology, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
authors.forename: Cheng Cheng
authors.initials: CC
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
authors.affiliation: Department of Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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: Aibing
authors.initials: A
authors.lastname: Liang
authors.affiliation: Department of Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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: Department of Hematology, Shanghai Tongji Hospital, Shanghai Tongji University School of Medicine, Shanghai, China; 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. zhengjunke@shsmu.edu.cn.
authors.forename: Junke
authors.identifier: 0000-0002-7023-2400
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000502:physiology*; D002453:Cell Cycle; D049109:Cell Proliferation; D056742:Cyclin D2 / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000473:pathology*; D020935:MAP Kinase Signaling System; D051379:Mice; D015996:Survival Rate
chemical_list: D060890:B7-H1 Antigen; C080336:CCND2 protein, human; D056742:Cyclin D2
keywords: Cell cycle entry; Cyclin D2; JNK; Leukemia-initiating cells; Programmed death ligand-1/CD274