We therefore generated Aldh2−/−Fancd2−/−Trp53−/− triple-knockout mice. The severe HSC depletion of Aldh2−/−Fancd2−/− mice was completely rescued in the triple knockouts (Fig. 6a, b). In addition, the triple-knockout stem cells were functional, as the mice showed a complete rescue in the frequency of ST-HSCs upon bone-marrow transplantation (Extended Data Fig. 6f). Moreover, p53 deficiency fully restored the blood cytopenias of untreated Aldh2−/−Fancd2−/− mice and made these mice more resistant to alcohol exposure (Extended Data Fig. 7). Notably, Trp53 deletion did not rescue the embryonic lethality of Aldh2−/−Fancd2−/− embryos (in Aldh2−/− mothers), suggesting that a different checkpoint might mediate developmental failure (Supplementary Information Table 2).
