Enhanced formaldehyde clearance ameliorates differentiation-induced genotoxicity in Fanconi anemia mutant cells

Fanconi anemia (FA) is a genetic disorder characterized by aplastic anemia and bone marrow failure arising from DNA crosslinking repair deficiencies. During hematopoietic differentiation, formaldehyde accumulates as a byproduct of transcriptional reprogramming, generating DNA crosslinks that abort differentiation and progressively deplete the hematopoietic hierarchy in the absence of FA pathway function. We performed a systematic screen of the aldehyde dehydrogenase (ALDH) activities to identify enzymes capable of metabolizing endogenous formaldehyde and protecting hematopoiesis in FA mutant cells. Our results identify ALDH8A1 as an effective enzyme that ameliorates formaldehyde-induced DNA damage during hematopoietic differentiation. Enhanced formaldehyde clearance significantly reduces DNA damage, markedly improving the survival of differentiating FA mutant progenitor cells and enabling completion of lineage progression. These findings highlight enhanced formaldehyde metabolism as an effective approach to ameliorate endogenous genotoxicity in FA mutant blood cells, suggesting a potential therapeutic strategy for restoring sustained hematopoiesis in patients with FA.