Protection of hematopoietic stem progenitor cells from endogenous DNA damage

Project Summary Maintaining genome integrity is critical for hematopoietic stem cells (HSCs) as they self-renew and differentiate into all blood cells throughout one’s life with enormous regenerative capacity. HSCs depend on the Fanconi anemia DNA repair pathway that removes DNA interstrand crosslinks. Endogenous reactive aldehydes are important sources of DNA damage that patients with Fanconi anemia are vulnerable to. Unfortunately, we do not know all the types and extent of reactive aldehydes that are important in human diseases. Moreover, there are no FDA-approved therapies that reduce aldehydic load and prevent DNA damage for patients with Fanconi anemia. In this R00 proposal, we propose to dissect the role of all the ALDH and ADH isoenzymes in human HSCs using a xenotransplant model and single-cell CRISPR screen. We also aim to uncover novel disease modifiers that can enhance aldehyde detoxification capacity through the CRISPR activation screen. Finally, we aim to prevent endogenous aldehyde-induced DNA damage in Fanconi anemia by activating detoxifying enzymes or extracellular vesicle-mediated delivery of functional enzymes. Knowledge gained through our studies will establish novel therapeutic strategies useful for preventing bone marrow failure and malignancies in Fanconi anemia.