Clonal hematopoiesis: Mutation-specific adaptation to environmental change

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) describes a widespread expansion of genetically variant hematopoietic cells that increases exponentially with age and is associated with increased risks of cancers, cardiovascular disease, and other maladies. Here, we discuss how environmental contexts associated with CHIP, such as old age, infections, chemotherapy, or cigarette smoking, alter tissue microenvironments to facilitate the selection and expansion of specific CHIP mutant clones. Further, we consider major remaining gaps in knowledge, including intrinsic effects, clone size thresholds, and factors affecting clonal competition, that will determine future application of this field in transplant and preventive medicine.

Keywords: aging; cancer; chemotherapy; clonal competition; clonal hematopoiesis; infection; inflammation; radiation.

Figure 1:. Environmental stressors promote mutation-specific clonal expansion.

Over an organism’s lifetime, HSCs encounter cellular stresses which may induce somatic mutations in common driver genes. Depending on the context, somatic mutations may confer a selection advantage for certain clones to persist and expand. Environmental effects on clonal competition are mutation specific. Genotoxic stressors such as chemotherapy and radiation provide a selection advantage for clones bearing mutations in p53, PPM1D, and CHEK2, whereas infection and inflammation promote the expansion of clones with mutations in TET2 and DNMT3A. Studies on the metabolic effects of clonal expansion suggest that metabolites, like vitamin C, may impact the function of mutations, such as TET2.