文献类型：期刊文献

英文题名：Bone marrow niche ATP levels determine leukemia-initiating cell activity via P2X7 in leukemic models

作者：He, Xiaoxiao[1];Wan, Jiangbo[2];Yang, Xiaona[3];Zhang, Xiuze[4];Huang, Dan[1];Li, Xie[4];Zou, Yejun[4];Chen, Chiqi[1];Yu, Zhuo[1];Xie, Li[1];Zhang, Yaping[1];Liu, Ligen[1];Li, Shangang[5];Zhao, Yuzheng[4];Shao, Hongfang[6];Yu, Ye[3];Zheng, Junke[1,7]

机构：[1]Shanghai Ciao Tong Univ, Shanghai Tongren Hosp, Fac Basic Med,Key Lab Cell Differentiat & Apoptos, Hongqiao Int Inst Med,Minist Educ,Sch Med, Shanghai, Peoples R China;[2]Shanghai Pao Tong Univ, Xinhua Hosp, Dept Hematol, Sch Med, Shanghai, Peoples R China;[3]China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Shanghai, Peoples R China;[4]East China Univ Sci & Technol, Sch Pharm, Optogenet & Synthet Biol Interdisciplinary Res Ct, State Key Lab Bioreactor Engn,Res Unit,Chinese A, Shanghai, Peoples R China;[5]Kunming Univ Sci & Technol, Inst Primate Translat Med, Yunnan Key Lab Primate Biomed Res, Kunming, Yunnan, Peoples R China;[6]Shanghai Sixth Peoples Hosp, Ctr Reprod Med, Shanghai, Peoples R China;[7]Shanghai Jiao Tong Univ, Shanghai Key Lab Reprod Med, Sch Med, Shanghai, Peoples R China

年份：2021

卷号：131

期号：4

外文期刊名：JOURNAL OF CLINICAL INVESTIGATION

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000620149600002)】；

基金：This work was supported by grants from the 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：英文

摘要：How particular bone marrow niche factors contribute to the leukemogenic activities of leukemia-initiating cells (LICs) remains 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 preferentially localized 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 approximately 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 phosphoglycerate dehydrogenase (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 perspective for understanding how ATP/P2X7 signaling sustains LIC activities, which may benefit the development of specific strategies for targeting LICs or other types of cancer stem cells.