Clonal Hematopoiesis : a Common Condition in the Elderly Population

Human bone marrow produces billions of mature blood cells every day. The traditional view is that the progeny blood cells are derived from 10,000–20,000 hematopoietic stem and progenitor cells (HSPC). 16,17 Typically, HSPC are equally capable of producing all of the differentiated blood cells, thereby maintaining the healthy state of polyclonal hematopoiesis. In contrast, CH is a condition in which a substantial proportion of mature blood cells are derived from a single dominant HSPC.18 Presumably, this condition arises because HSPC and their immediate progenitors are subjected to Darwinian selective pressures within the stem cell niche, favoring the expansion of clones with somatic mutations that provide a competitive advantage. CH was initially detected as the skewing of X chromosome inactivation in the white blood cells of women. In one study, 37.9% women over the age of 60 years displayed skewed inactivation of the X chromosome, whereas little or no skewing was observed in younger women.19 A notable advance was made when the skewing of X chromosome inactivation was attributed to somatic mutations in the epigenetic regulator TET2.20 These data provided the first evidence that CH can result from somatic mutations in preleukemic or myelodysplastic syndrome (MDS) “driver” genes. Consistent with these findings, single nucleotide polymorphism (SNP) array analyses have detected somatic clonal mosaicism in peripheral blood of healthy individuals, and the frequency of this mosaicism steeply increased in individuals past the age of 50 years.21,22 More recent studies analyzed exome sequences of more than 32,000 cancer-free individuals and found high frequencies of clonal expansion events that were associated with mutations in numerous T raditional risk factors of cardiovascular disease (CVD) include hypertension, diabetes mellitus, hyperlipidemia, and smoking. However, the completeness of their predictive value has been questioned.1,2 The occurrence of CVD increases exponentially with age, which is traditionally viewed as a non-modifiable risk factor.3 Although aging is a major risk factor for CVD, we have poor understanding of how it promotes disease progression. These considerations lead to the question, “Are there age-associated, as-yet-unidentified, risk factors for CVD? ” Somatic DNA mutations accumulate in all cells with age, such that over time tissues become a mosaic of cells with slightly different genotypes.4–7 In proliferating tissues, mutations in “driver” genes, which provide a selective advantage or “fitness” to cells, can lead to the clonal expansion of these single cells. Previously, there was little information about the role that mutant cell clonal expansion has on age-associated chronic disorders. However, a number of recent epidemiological studies have associated the clonal expansion of hematopoietic cells, a process referred to as clonal hematopoiesis (CH), with increased mortality.8–11 CH increases the risk of a hematological cancer, but this overall risk is small and cannot account for the increase in mortality in the general population. Surprisingly, these mutations have also been associated with higher rates of CVD,8,12 suggesting a previously unrecognized link between somatic mutations in hematopoietic cells and chronic disease. Thus, a series of experimental studies has been performed to assess the potential causal connection between mutations in hematopoietic system and CVD, and define the mechanisms involved in these processes.12–15 Here, we review recent epidemiological and experimental studies on CH that relate to CVD.