Genotoxic formaldehyde accelerates ageing in hematopoietic stem cells in a p53-driven manner

Aged hematopoietic stem cells (HSC) display diminished self-renewal and a myeloid differentiation bias. However, the physiological drivers and molecular processes that underpin this fundamental switch are not well understood. We previously discovered that HSCs produce formaldehyde, a potent source of DNA damage that can lead to HSC attrition and leukemia. HSCs are protected from this metabolite by two tiers of protection: the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. Using single cell RNA sequencing, we find that the HSC and progenitor cells in young Aldh2- /- Fancd2-/- mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition and myeloid-biased progenitors. In addition, the p53 response is vigorously activated in Aldh2-/- Fancd2-/- HSCs, whilst p53 deletion rescued this aged transcriptomic signature and telomere attrition. Transplantation of single Aldh2-/- Fancd2-/- HSCs also reveals a predominantly myeloid output, which is reversed upon p53 deletion. We derive a blood specific p53 transcriptomic signature to find increased p53 activity in old wild type HSCs, as well as p53-dependent expression of multiple genes associated with myeloid biased HSCs. To further define the origins of the myeloid differentiation bias, a GFP genetic reporter which detects Vwf+ myeloid- primed HSCs was crossed into Aldh2-/- Fancd2-/- mice, revealing a striking enrichment of these lineage-biased Vwf+ HSCs. These results indicate that formaldehyde genotoxin triggers a p53 response in HSCs to accelerate their aging, including a myeloid lineage biased output. Lastly, we use the blood p53 signature to show increased p53 activity in human acute myeloid leukemia, which correlates with adverse survival, and could offer an useful clinical tool. Aged hematopoietic stem cells (HSC) display diminished self-renewal and a myeloid differentiation bias. However, the physiological drivers and molecular processes that underpin this fundamental switch are not well understood. We previously discovered that HSCs produce formaldehyde, a potent source of DNA damage that can lead to HSC attrition and leukemia. HSCs are protected from this metabolite by two tiers of protection: the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. Using single cell RNA sequencing, we find that the HSC and progenitor cells in young Aldh2- /- Fancd2-/- mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition and myeloid-biased progenitors. In addition, the p53 response is vigorously activated in Aldh2-/- Fancd2-/- HSCs, whilst p53 deletion rescued this aged transcriptomic signature and telomere attrition. Transplantation of single Aldh2-/- Fancd2-/- HSCs also reveals a predominantly myeloid output, which is reversed upon p53 deletion. We derive a blood specific p53 transcriptomic signature to find increased p53 activity in old wild type HSCs, as well as p53-dependent expression of multiple genes associated with myeloid biased HSCs. To further define the origins of the myeloid differentiation bias, a GFP genetic reporter which detects Vwf+ myeloid- primed HSCs was crossed into Aldh2-/- Fancd2-/- mice, revealing a striking enrichment of these lineage-biased Vwf+ HSCs. These results indicate that formaldehyde genotoxin triggers a p53 response in HSCs to accelerate their aging, including a myeloid lineage biased output. Lastly, we use the blood p53 signature to show increased p53 activity in human acute myeloid leukemia, which correlates with adverse survival, and could offer an useful clinical tool.