Clonal hematopoiesis and the environment. The bone marrow contains large numbers of cells (difficult to depict graphically), which by adulthood have stochastically accumulated mutations, most presumably without biological consequence (these cells and clones are shown with variable gray shading). By chance alone, mutations will also occur in genes that do affect function; a cell mutated in the PIGA gene is shown in normal adult bone marrow, because there is experimental evidence that such cells can be isolated from healthy donors.61 Whether such mutated cells expand to clones is highly dependent on extrinsic conditions. Chemotherapy is the most dramatic example of an environmental perturbation, shrinking (temporarily) the stem and progenitor compartment, effecting genotoxicity, and producing immediate regenerative stress. Selective pressure of the chemotherapy environment favors cells resistant to apoptotic signals, as has been demonstrated for TP53-mutated clones.91,92,97 In immune bone marrow failure, cells not recognized or resistant to immune destruction would be favored: PIGA-mutated cells and cells that have partially lost HLA genes. Additionally, an environment enriched for hematopoietic growth factors and other proliferative signals would allow passive accumulation of cells that normally respond poorly to such stimuli. The aging environment is not yet fully defined, but clonal hematopoiesis likely reflects a diminished stem-cell pool and a lifetime of intermittent inflammation and concurrent diseases, toxic exposures, and many other factors (Figure 3). HSC, hematopoietic stem cell.
