A 2-tier protection mechanism preserves HSC function. (A) HSCs display high Aldh2 activity that protects their genome against the toxic effects of reactive aldehydes. If aldehydes should evade this protection mechanism, then DNA damage is dealt with by the FA DNA repair pathway. (B) In Aldh2^−/−Fancd2^−/− mice, the HSC pool is exposed to a greater burden of reactive aldehydes, and in the absence of DNA repair, DNA damage persists and leads to neoplastic transformation or HSC loss and spontaneous BMF.