Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis.

ABSTRACT: Somatic DNMT3A-R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk^1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3a^R882H/+ HSPCs. Among the 640 vulnerability genes identified, many were involved in mitochondrial metabolism, and metabolic flux analysis confirmed enhanced oxidative phosphorylation use in Dnmt3a^R882H/+ versus Dnmt3a^+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inh

SUBMITTER: Gozdecka M 

PROVIDER: S-EPMC12158785 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature