Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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 disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a 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 aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues.

Original publication




Journal article


Mol Cell

Publication Date





996 - 1012.e9


DNA damage, ageing, bone marrow failure, cancer, formaldehyde, hematopoiesis, hematopoietic stem cells, immunodeficiency, mutagenesis, oncometabolite, Adolescent, Alcohol Dehydrogenase, Aldehyde Dehydrogenase, Mitochondrial, Aldehydes, Animals, Child, Child, Preschool, DNA Adducts, DNA Damage, DNA Repair, Female, Formaldehyde, Hematopoiesis, Hematopoietic Stem Cells, Humans, Infant, Leukemia, Male, Mice, Mutation, Substrate Specificity