ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications

Normal hematopoietic stem and progenitor cells (HSPCs) are exposed to physiological levels of formaldehyde but occasionally may be challenged by high levels of formaldehyde generated by endogenous and exogenous sources. In addition, leukemia cells stressed by oncogenic mutations continuously produce excessive amounts of formaldehyde. Here, we show that DNA polymerase theta (Polθ) cooperates with alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 2 (ALDH2) to protect healthy and malignant HSPCs challenged by formaldehyde. ADH5 and ALDH2 metabolize formaldehyde while Polθ-mediated DNA repair by microhomology-dependent end-joining (TMEJ) protects cells from the lethal effect of DNA double strand breaks resulting from formaldehyde-mediated DNA-protein crosslinks. Genetic or pharmacological targeting of ADH5 or ALDH2 enhanced the effect of Polθ inhibitors in leukemic cells. Thus, ADH5/ALDH2 cooperate with Polθ to protect normal HSPCs sporadically challenged by high levels of formaldehyde, and inhibition of Polθ and ADH5 or ALDH2 may exert an anti-leukemic effect.