Nonionotropic action of an acid-sensing ion channel inhibits leukemogenesis in the acidic bone marrow niche

作者：Hao Gu, Lietao Weng, Chiqi Chen, Xiaoxin Hao, Rongkun Tao, Xin Qi, Xiaoyun Lai, Ligen Liu, Tinghua Zhang, Yiming Jiang, Jin Wang, Wei‐Guang Li, Zhuo Yu, Li Xie, Yaping Zhang, Xiaoxiao He, Ye Yu, Yi Yang, Di Wu, Yuzheng Zhao, Tian‐Le Xu, Guoqiang Chen, Junke Zheng · 发表于：Journal of Clinical Investigation · 年份：2025 · DOI：10.1172/jci189051 · 被引用次数：1 · 研究领域：Ion Transport and Channel Regulation、Cancer, Hypoxia, and Metabolism、Parathyroid Disorders and Treatments

The metabolic microenvironment plays important roles in tumorigenesis, but how leukemia-initiating cells (LICs) response to the acidic BM niche remains largely unknown. Here, we show that acid-sensing ion channel 3 (ASIC3) dramatically delays leukemogenesis. Asic3 deletion results in a remarkably enhanced self-renewal, reduced differentiation, and 9-fold greater number of murine acute myeloid LICs. We developed an ultrasensitive, ratiometric, genetically encoded fluorescent pH sensor (pHluorin3) and demonstrated that LICs prefer localizing in the endosteal niche with a neutral pH range of 7.34-7.42, but not in the vascular niche with a lower pH range of 6.89-7.22. Unexpectedly, acid-ASIC3 signaling inhibits both murine and human LIC activities in a noncanonical manner by interacting with the N-terminal of STIM1 to reduce calcium-mediated CAMK1-CREB-MEIS1-LDHA levels, without inducing cation currents. This study reveals a pathway in suppression of leukemogenesis in the acidic BM niche and provides insight into targeting LICs or other cancer stem cells through pH-dependent ASICs.