Choline Kinase Alpha Inhibition is a Mutation Agnostic Therapeutic Vulnerability in Clonal Hematopoiesis

Abstract

Clonal Hematopoiesis (CH) affects the aging population and is associated with increased risk of hematological malignancy, cardiovascular disease, and all-cause mortality. Therapeutic options for CH remain limited. Using hematopoietic stem and progenitor cell (HSPC) color barcoding and mosaic mutagenesis in zebrafish, we identified perturbed choline metabolism and increased phosphatidylcholine (PC) biosynthesis via choline kinase alpha (CHKA) in asxl1-mutant HSPCs. Suppressing CHKA-dependent choline flux reduced ASXL1-driven clonal expansion. This effect was conserved in a murine DNMT3A and human TET2 model. Mechanistically, CHKA- dependent choline flux controls phosphatidylcholine production that supports platelet activating factor (PAF) production. Exogenous PAF overcomes the suppressive effect of CHKA inhibition in ASXL1 and TET2 models. We isolated primary, human HSPCs from the peripheral blood of patients with endogenous ASXL1 mutations and demonstrated that perturbing PAF signaling reduces their competitive potential in an ex vivo clonal competition assay. This CHKA/PAF axis is conserved in TET2-mutant HSPCs. Together, these findings identify a mutation agnostic metabolic dependency across the three most common CH genotypes and demonstrate that targeting the CHKA-dependent choline flux suppresses clonal expansion.