Clonal haematopoiesis of emerging significance

Abstract

Clonal haematopoiesis (CH) is a ubiquitous feature of aging and provides mechanistic insight into the inextricable relationship between chronic inflammation and age-related diseases. Although CH confers a cumulative risk of subsequent haematological malignancy, particularly myeloid neoplasms, that risk is heavily mutation- and context-specific. Individuals with mutations in DNA damage response pathway genes receiving select cytotoxic therapies for solid tumours are among the highest risk groups for subsequent development of myeloid neoplasms. Multiple lines of evidence suggest that TET2-mutated macrophages causally contribute to cardiometabolic disease through the generation of proinflammatory cytokines. It is speculated that such CH-related inflammation is a shared driver of several other chronic diseases. Whether we can intervene in individuals with CH to diminish the risk of subsequent haematological malignancy or non-haematological disease remains to be seen. However, precision anti-cytokine therapies are a rational starting point to break the feedforward loop between clonal myeloid expansion, inflammation, and end-organ damage.

Keywords: Age-related; cardiometabolic; clonal haematopoiesis; inflammasome; myeloid.