The dynamic and age–related process of acquiring mutations in healthy tissues provides insights into environmental exposures as well as the internal molecular factors that shape the development of clonal hematopoiesis (CH). In particular, acquiring a mutation that confers a selective growth advantage to hematopoietic stem or progenitor cells alters the process of hematopoiesis, resulting in the generation of clonal blood cells and an elevated risk of developing blood cancer. Although highly significant, the absolute risk of developing blood cancer is low (about 1-2% per annum) but clonal blood cells may have a wider effects on non-hematopoietic organs since blood cells are widely distributed within tissues, and clonal changes may potentially alter the immune response and promote an inflammatory state (Fig 1).
Fig 1: Age related clonal hematopoiesis
How to define clonal hematopoiesis?
CH is defined by the presence of subpopulations of blood cells marked by acquisition of a specific somatic abnormality. Studies to date have focused on CH defined by mutations in genes, or chromosome level abnormalities. In our study of the UK Biobank cohort (n = 502,524), we focused on myeloid CH defined by both mosaic chromosomal abnormalities (mCA) identified from SNP array data and driver mutations identified from whole exome sequence data. As expected, myeloid CH defined by either mCA or somatic mutations had a similar relationship with age, with the prevalence increasing by 1.1 fold per year.
Smoking, inflammation and clonality
Our investigation provides further evidence for an association between factors driving the development of myeloid CH and markers of inflammation and non-malignant inflammatory disorders. We confirmed several findings from previous studies, for example associations between CH and red cell distribution width (a marker of inflammation), smoking (a cause of inflammation) and chronic obstructive pulmonary disease (associated with chronic inflammation). In addition, we found a striking and novel association between smoking and driver mutations in ASXL1, a gene encoding a chromatin-level regulator of gene expression. We suggest that the inflammatory environment induced by smoking promotes the outgrowth of ASXL1-mutant clones.
Our study concludes that both environmental and genetic factors play a role in the development of CH. Larger datasets such as the planned sequencing of the whole UK Biobank cohort will enable the refinement and strengthening of genetic and inflammatory associations down to the driver gene level. Translating these genetic and phenotypic characteristics into drug-targeting strategies will provide an opportunity to control the proliferative stress mediated by age-related inflammation.