Environmental influences on clonal hematopoiesis

Abstract

Clonal hematopoiesis (CH) has emerged as an important factor linked to adverse health conditions in the elderly. CH is characterized by an overrepresentation of genetically distinct hematopoietic stem cell clones in the peripheral blood. Whereas the genetic mutations that underlie CH have been closely scrutinized, relatively little attention has been paid to the environmental factors that may influence the emergence of one dominant stem cell clone. As there is huge individual variation in latency between acquisition of a genetic mutation and emergence of CH, environmental factors likely play a major role. Indeed, environmental stressors such as inflammation, chemotherapy, and metabolic syndromes are known to affect steady-state hematopoiesis. To date, epidemiologic studies point toward smoking and prior chemotherapy exposure as likely contributors to some forms of CH, though the impact of other environmental factors is also being investigated. Mechanistic studies in murine models indicate that the role of different environmental factors in CH emergence may be highly specific to the mutation that marks each stem cell clone. For instance, recent studies have found that clones with mutations in the PPM1D gene are more resistant to genotoxic stress induced by chemotherapy. These clones thus have a competitive advantage in the setting of chemotherapy, but not in other types of stress. Here we review currently available literature on the interplay between environment and the genetic landscapes in CH and highlight critical areas for future study. Improved understanding of the effects of environmental stress on emergence of CH with mutation-specific clarity will guide future efforts to provide preventive medicine to individuals with CH.

Figure 1.

A variety of mutations are associated with clonal hematopoiesis. Clonal dominance may occur through several mechanisms, either via increased self-renewal, a proliferative advantage, or improved survival. DNMT3A and TET2 mutations are thought to offer a competitive advantage through increased self-renewal at the stem cell level. The mechanism through which JAK2 mutations confer and advantage are unknown but are speculatively indicated here as proliferation of the stem and progenitor cell population. PPM1D mutations likely confer an advantage through enhancing survival under adverse circumstances such as chemotherapy.

Figure 2.

Positive feedback loop between TET2-deficient HSPCs and their innate myeloid cell progeny during the response to pathogen-associated molecular patterns. Inflammatory cytokines such as IL-6 are excessively produced by TET2-deficient myeloid cells, leading to further expansion of the HSPC compartment and perpetuation of the cycle.