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DNA Damage and Mutagenesis

HSCs in a dormant state are protected from DNA damage since they produce low levels of metabolic reactive oxygen species and do not replicate their genome. However, upon exposure to environmental stress, such as infections or inflammation, dormant HSCs are forced into active proliferation, rendering them susceptible to replication stress-induced DNA damage. Such damage could impact on the ability of HSCs to generate mature blood cells, either through direct loss of damaged HSCs (via apoptosis) or through the acquisition of mutations that may impact on HSC functionality.

Genome instability is another prominent hallmark of aging that holds a clear mechanistic link to malignant transformation. In 2015, we published a well-cited study demonstrating that inflammation and infection can induce biologically relevant levels of DNA damage within HSCs in vivo, by forcing these cells out of their homeostatic state of long-term quiescence (dormancy) [1]. Subsequent work on this topic proceeded in two main directions: the exploration of the therapeutic relevance of this phenomenon to the treatment of hematologic malignancies; and the characterization of whether inflammatory challenge can impact on the qualitative and quantitative mutation burden of normal adult stem cells during aging. With regards to hematologic malignancies, in collaboration with the group of Steven Lane (Queensland Institute for Medical Research, Brisbane, Australia), we have shown that interferon- depletes JAK2-V617F mutant HSCs in a mouse model of polycythemia vera, by inducing DNA damage in these cells as a result of replication stress [2]. In the setting of age-related mutagenesis within adult stem cells, we have initiated a highly productive collaboration with the group of Dr. Inigo Martincorena (Wellcome Sanger Institute, Cambridge, UK) to develop experimental data analysis pipelines to provide a detailed characterization of stem cell mutation burden at a clonal level. In 2022, we were able to contribute to a manuscript demonstrating that, across different mammalian species, the rate of mutation acquisition within stem cells scales to the lifetime of an organism [3].

  1. Walter et al., Exit from dormancy provokes DNA damage-induced attrition in haematopoietic stem cells. Nature 520(7548):549-552 (2015)
  2. Austin et al., Distinct effects of ruxolitinib and interferon-alpha on murine JAK2V617F myeloproliferative neoplasm hematopoietic stem cell populations. Leukemia 34:1075-1089 (2020)
  3. Cagan et al., Somatic mutation rates scale with lifespan across mammals. Nature 604:517-524 (2022)

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