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Here, we show that acid-sensing ion channel 3 (ASIC3) dramatically delays leukemogenesis.\n                    <jats:italic>Asic3<\/jats:italic>\n                    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\u20137.42, but not in the vascular niche with a lower pH range of 6.89\u20137.22. 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.\n                  <\/jats:p>","DOI":"10.1172\/jci189051","type":"journal-article","created":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T19:00:54Z","timestamp":1765738854000},"source":"Crossref","is-referenced-by-count":3,"title":["Nonionotropic action of an acid-sensing ion channel inhibits leukemogenesis in the acidic bone marrow niche"],"prefix":"10.1172","volume":"135","author":[{"given":"Hao","family":"Gu","sequence":"first","affiliation":[{"name":"Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine, Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, Hainan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lietao","family":"Weng","sequence":"additional","affiliation":[{"name":"Institute for Translational 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