Phosphatidylcholine synthesis inhibition diminishes ASXL1 and DNMT3a mutation driven clonal hematopoiesis

作者：Brandon Gheller, Olivia Mitchell, Serine Avagyan, Jayakrishnan Gopakumar, Michael Quach, Fernando D. Camargo, Siddhartha Jaiswal, Leonard I. Zon · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-973 · 研究领域：Zebrafish Biomedical Research Applications、Acute Myeloid Leukemia Research、Acute Lymphoblastic Leukemia research

Abstract The acquisition of somatic mutations that increase the competitive potential of hematopoietic stem and progenitor cell (HSPC) clones causes Clonal Hematopoiesis (CH). CH, where one HSPC clone becomes dominant, occurs in >10% of individuals over 65 and predisposes these individuals to hematological malignancy and cardiovascular disease. No approved therapies currently exist. We posited that metabolically profiling dominant, mutant HSPCs could reveal targetable metabolic vulnerabilities. We combined mosaic mutagenesis of CH-driving genes and HSPC color barcoding to isolate dominant HSPC clones in zebrafish. Untargeted metabolomics was performed on dominant asxl1- or ezh2-mutant or wildtype (WT) HSPCs. Only 7 of 90 detected metabolites differed significantly. Two choline-related metabolites were decreased in dominant HSPC clones: betaine (FC -0.68, p<0.01) and acetylcholine (FC -0.42, p<0.01). This metabolic signature was confirmed in an independent asxl1-mutant CH cohort using a standard containing choline metabolite profiling assay. We hypothesized that decreased betaine and acetylcholine levels reflected increased partitioning of choline into phospholipid biosynthesis (e.g., phosphatidylcholines). Lipid profiling of asxl1-mutant and WT zebrafish HSPCs revealed a global decrease in phosphatidylcholine levels; species 16:1/18:1 (FC 1.33, p<0.05), 16:0/16:0 (FC 1.44, p<0.05), and 16:0/18:2 (FC 1.50, p<0.05) were the most affecte...