机构：[1]Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.[2]Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.[3]School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.[4]Optogenetics & Synthetic Biology Interdisciplinary Research Center, School of Pharmacy, East China University of Science and Technology, Shanghai, China.[5]Yunnan Key Laboratory of Primate Biomedicine Research, Kunming University of Science and Technology, Kunming, China.[6]Centre for Reproductive Medicine, Shanghai Sixth People'd Hospital, Shanghai, China.[7]Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
How particular bone marrow niche factors contribute to the leukemogenic activities of leukemia-initiating cells (LICs) remain largely unknown. Here, we showed that ATP levels were markedly increased in the bone marrow niches of mice with acute myeloid leukemia (AML), and LICs preferred to localizing to the endosteal niche with relatively high ATP levels, as indicated by a sensitive ATP indicator. ATP could efficiently induce the influx of ions into LICs in an MLL-AF9-induced murine AML model via the ligand-gated ion channel P2X7. P2x7 deletion led to notably impaired homing and self-renewal capacities of LICs and contributed to an ~5-fold decrease in the number of functional LICs but had no effect on normal hematopoiesis. ATP-P2X7 signaling enhanced the calcium flux-mediated phosphorylation of CREB, which further transactivated the Phgdh expression to maintain serine metabolism and LIC fates. P2X7-knockdown resulted in a markedly extended survival of recipients transplanted with either human AML cell lines or primary leukemia cells. Blockade of ATP-P2X7 signaling could efficiently inhibit leukemogenesis. Here, we provide a unique perspective for understanding how ATP-P2X7 signaling sustains the LIC activities, which may benefit the development of specific strategies for targeting LICs or other types of cancer stem cells.
基金：
National
Basic Research Program of China (2019YFA0801800,
2018YFA0107000, and 2019YFA0904800), the National Natural
Science Foundation of China (NSFC) (81825001, 81570093,
31971052, 81900147, 31722033, and 31671484), the innovative
group of the NSFC (grant 81721004), the Shanghai Science
and Technology Commission (19XD1422100, 20ZR1430900,
20JC1410100, and 17ZR1415500), and the Research Unit of New Techniques for Live-cell Metabolic Imaging (Chinese Academy of
Medical Sciences; 2019RU01, 2019-I2M-5-013).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2019]版：
大类|1 区医学
小类|1 区医学：研究与实验
最新[2025]版：
大类|1 区医学
小类|1 区医学：研究与实验
第一作者：
第一作者机构：[1]Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
共同第一作者：
通讯作者：
通讯机构：[1]Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.[3]School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.[6]Centre for Reproductive Medicine, Shanghai Sixth People'd Hospital, Shanghai, China.[7]Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.[*1]280 South Chongqing Road, Shanghai 200025, China[*2]639 Long-Mian Road, Nanjing 211198, China[*3]600 Yishan Road, Shanghai 200233, China
推荐引用方式(GB/T 7714)：
He Xiaoxiao,Wang Jiangbo,Yang Xiaona,et al.Bone marrow niche ATP levels determine leukemia-initiating cell activity via P2X7 in leukemic models.[J].The Journal Of Clinical Investigation.2020,doi:10.1172/JCI140242.
APA：
He Xiaoxiao,Wang Jiangbo,Yang Xiaona,Zhang Xiuze,Huang Dan...&Zheng Junke.(2020).Bone marrow niche ATP levels determine leukemia-initiating cell activity via P2X7 in leukemic models..The Journal Of Clinical Investigation,,
MLA：
He Xiaoxiao,et al."Bone marrow niche ATP levels determine leukemia-initiating cell activity via P2X7 in leukemic models.".The Journal Of Clinical Investigation .(2020)
医学