Haematopoietic stem cells (HSCs) regenerate blood cells throughout the lifespan of an organism. With age, the functional quality of HSCs declines, partly owing to the accumulation of damaged DNA1,2,3. However, the factors that damage DNA and the protective mechanisms that operate in these cells are poorly understood. We have recently shown that the Fanconi anaemia DNA-repair pathway counteracts the genotoxic effects of reactive aldehydes4,5. Mice with combined inactivation of aldehyde catabolism (through Aldh2 knockout) and the Fanconi anaemia DNA-repair pathway (Fancd2 knockout) display developmental defects, a predisposition to leukaemia, and are susceptible to the toxic effects of ethanol—an exogenous source of acetaldehyde4. Here we report that aged Aldh2−/−Fancd2−/− mutant mice that do not develop leukaemia spontaneously develop aplastic anaemia, with the concomitant accumulation of damaged DNA within the haematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, we find that only HSPCs, and not more mature blood precursors, require Aldh2 for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in both Fanconi anaemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, the emergence of bone marrow failure in Fanconi anaemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool. These findings identify a new link between endogenous reactive metabolites and DNA damage in HSCs, and define the protective mechanisms that counteract this threat.
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We thank M. Grompe for Fancd2-deficient mice and M. Milsom and D. Walter for technical advice. We are grateful to T. Langford, R. Berks, A. Middleton, C. Knox and J. Wiles for their help with mouse experimental work. We would also like to thank the Biomed services and ARES staff for animal husbandry and assistance. We thank N. Grant for photography. We thank the Human Research Tissue Bank (NIHR Cambridge Biomedical Research Centre) for processing histology. We also thank F. Zhang for help with FACS. G.P.C. is supported by CRUK and Homerton College, Cambridge. J.I.G. is supported by the Milstein Fund and the Darwin Trust of Edinburgh. F.L. is supported by the March of Dimes Foundation.
The authors declare no competing financial interests.
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Garaycoechea, J., Crossan, G., Langevin, F. et al. Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature 489, 571–575 (2012). https://doi.org/10.1038/nature11368
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