Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis

Abstract

Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were most common and, although their prevalence increased with age, were found in individuals as young as 25 years. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged >70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age.

Graphical abstract

Figure 1

Prevalence and Age Distribution of Hot Spot Mutations Driving Clonal Hemopoiesis (A) Prevalence of mutations driving clonal hemopoiesis by age. (B) Samples with more than one mutation, variant allele fraction (VAF) of each mutation present, and age of participant. Also see Figure S1 for age distribution of all participants.

Figure 2

Proposed Kinetics of Hemopoietic Clones Driven by Different Gene Mutations Mutations such as DNMT3A R882H/C or JAK2 V617F drive a slow but inexorable clonal expansion, leading to the outgrowth of a detectable clone after a certain latency. By contrast, mutations affecting spliceosome genes, such as SF3B1 and SRSF2, and acquired at the same age for the purposes of this model give no proliferative advantage initially but do so later in the context of an aging hemopoietic compartment. Their effects may operate by prolonging stem cell survival and repopulating fitness beyond that of normal stem cells or by exploiting cell-extrinsic changes in the aging microenvironment.