Clonal hematopoiesis in human aging and disease

Abstract

As people age, their tissues accumulate an increasing number of somatic mutations. Although most of these mutations are of little or no functional consequence, a mutation may arise that confers a fitness advantage on a cell. When this process happens in the hematopoietic system, a substantial proportion of circulating blood cells may derive from a single mutated stem cell. This outgrowth, called "clonal hematopoiesis," is highly prevalent in the elderly population. Here we discuss recent advances in our knowledge of clonal hematopoiesis, its relationship to malignancies, its link to nonmalignant diseases of aging, and its potential impact on immune function. Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.

Fig. 1.

A single HSC in a healthy person acquires approximately one protein-coding mutation per decade of life (00). Four mutational processes contribute to the bulk of these age-associated mutations (right). Assuming there are 50,000 to 200,000 HSCs in an average person (00), we estimate that by age 70, an average person will harbor 350,000 to 1.4 million protein coding mutations in his/her HSC pool. Shown in the bottom left is the expected range of random mutations in HSCs in the exons of DNMT3A, TET2, ASXL1, JAK2, SF3B1, and TP53 by age 70 per person. A subset of these mutations may lead to clonal expansions.

Fig. 2.

The estimated prevalence of CHIP as a function of age varies according to the sequencing method used. VAF, variant allele fraction. ECS, error corrected sequencing. WES, whole- exome sequencing. WGS, whole-genome sequencing.

Fig.3.

(A) Forest plots for odds ratio for developing acute myeloid leukemia (AML) and hazard ratio for developing coronary heart disease (CHD) in those with mutations in the genes listed, adapted from Abelson et al. Nature 2018 and Jaiswal et al., NEJM 2017. Only those mutations with a variant allele fraction greater than 2% (meeting the definition of CHIP) were included. Individuals with mutations in more than one driver gene were analyzed as a separate category. Lines represent the 95% confidence interval for odds or hazard ratios and the sizes of the dots are proportional to the number of mutations in each gene in the general population. B) Hazard ratio (HR) and 95% confidence interval (CI) for developing CHD based on Framingham risk factors plus presence of CHIP mutations. Data taken from population-based cohorts unselected for CHD status (just give ref numbers).

Fig. 4.

Phenotypic changes in HSCs and immune cells with TET2 or DNMT3A mutations.