Ablation of Adh5 with Fancd2 leads to rapid onset of bone marrow failure and leukaemia in mice

LUCAS PONTEL; IVAN ROSADO; JUAN GARAYCOECHEA; KJ PATEL

Simposio; Fanconi Anemia Research Fund Scientific Symposium 2013; 2013

Fanconi Anemia Research Fund

Formaldehyde is a genotoxic aldehyde produced close to DNA. It is not known how mammals protect their genomes from this toxic molecule. We will present the consequences of inactivating alcohol dehydrogenase 5 (Adh5), an enzyme that catabolises formaldehyde, as well as the Fanconi anaemia DNA repair pathway in mice. Animals lacking both Adh5 and Fancd2 (Adh5-/- Fancd2-/-) are born and viable for the first few weeks of life. However, they rapidly develop bone marrow failure. This is due to a profound depletion of haematopoietic stem cells and progenitors. In two instances the marrow was also shown to contain an infiltration of B220+ cells suggesting an early B cell leukaemia. Finally, Adh5-/-Fancd2-/- haematopoietic cells accumulate broken chromosomes and are also exquisitely sensitive to exogenous formaldehyde. The striking and more severe phenotype of Adh5-/-Fancd2-/- compared Aldh2-/-Fancd2-/- probably indicates that endogenous formaldehyde may be a greater threat in Fanconi anaemia than acetaldehyde.