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

ABSTRACT: 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 t

SUBMITTER: Gu H 

PROVIDER: S-EPMC12700551 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature