Two aldehyde clearance systems are essential to prevent lethal formaldehyde accumulation in mice and humans

Reactive aldehydes arise as by-products of metabolism, and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is profoundly disrupted, with a reduction of hematopoietic stem cells and also common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is the common substrate of ALDH2 and ADH5, and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone marrow derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to ageing-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a new inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues. Overall design: LK (lin-c-Kit+) and lin-c-KitloSca1+ blood progenitor cells from WT, Aldh2-/-, Adh5-/- and Aldh2-/-Adh5-/- mice were sequenced by 10X Genomics (one mouse each) and compared across genotypes