Nonionotropic action of an acid-sensing ion channel inhibits leukemogenesis in the acidic bone marrow niche
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.
Authors
- Yuzheng Zhao (ORCID: https://orcid.org/0000-0001-5400-0135)
- Ligen Liu (ORCID: https://orcid.org/0000-0002-3971-783X)
- Wei‐Guang Li (ORCID: https://orcid.org/0000-0002-3442-7518)
- Xin Qi (ORCID: https://orcid.org/0000-0003-2631-0456)
- Yi Yang (ORCID: https://orcid.org/0000-0001-7896-1184)
- Ye Yu (ORCID: https://orcid.org/0000-0002-4054-8543)
- Yanping Jiang (ORCID: https://orcid.org/0000-0002-0931-9507)
- Junke Zheng (ORCID: https://orcid.org/0000-0002-7023-2400)
- Rongkun Tao (ORCID: https://orcid.org/0000-0003-0176-3432)
- Tian‐Le Xu (ORCID: https://orcid.org/0000-0002-1438-0038)
- Yaping Zhang (ORCID: https://orcid.org/0000-0002-1085-0135)
- Lietao Weng
- Xiaoxin Hao (ORCID: https://orcid.org/0000-0001-8763-3529)
- Chiqi Chen (ORCID: https://orcid.org/0000-0001-7220-8212)
- Jin Wang
- Zhuo Yu
- Li Xie (ORCID: https://orcid.org/0000-0001-7393-5446)
- Hao Gu (ORCID: https://orcid.org/0000-0002-2798-6522)
- Di Wu (ORCID: https://orcid.org/0000-0002-7404-4810)
- Xiaoxiao He (ORCID: https://orcid.org/0000-0002-9455-1182)
- Tinghua Zhang (ORCID: https://orcid.org/0000-0002-4691-388X)
- Guoqiang Chen (ORCID: https://orcid.org/0000-0003-4936-2363)
- Xiaohui Lai
Institutions
- East China University of Science and Technology (CN)
- China Pharmaceutical University (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- First Affiliated Hospital of Xiamen University (CN)
- Shanghai Ninth People's Hospital (CN)
- Tongren Hospital (CN)
- Ministry of Education (TH)
- Songjiang District Central Hospital (CN)
- State Key Laboratory of Synthetic Chemistry (CN)
- Huashan Hospital (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-12-14
- DOI
- https://doi.org/10.1172/jci189051
- Primary Topic
- Ion Transport and Channel Regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00