In a study published in Nature Communications, researchers show that hematopoietic clones harboring mutations in DNA damage response genes, including TP53 and PPM1D, expand in response to cytotoxic stress.

Hematopoietic stem cells (HSCs) acquire somatic mutations with age, resulting in a genetically heterogeneous population with each HSC possessing its own set of unique mutations. Some of these mutations confer a fitness advantage, allowing the HSCs harboring them to clonally expand.

Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic autologous transplantation.

Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism.

However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, the researchers genotyped 134 t-AML/t-MDS samples. Mutations in non-TP53 DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy.

These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor.

Genotoxic stress from cytotoxic therapy promotes the expansion of clones with mutations in DNA damage response genes, such as TP53 and PPM1D. Transplantation-related stress may select for clones with DNMT3A mutations, particularly in codon 882.

Expanded clones are often long-lived and transplantable, but their leukemogenic potential varies, in part, due to the mutations they harbor. Most expanded clones, even those harboring TP53 mutations, do not evolve into leukemia.

In conclusion, the data show that cellular stressors result in the expansion of hematopoietic clones carrying specific mutations. In the future, longitudinal studies of patients before and after specific stressors (e.g., cytotoxic therapy, mobilization ± cytotoxic stimulation, transplantation, etc.) will more precisely define their influence on clonal expansion and distinguish the impact of these stressors from that of other factors (e.g., pre-existing malignancies).