Review

Clonal hematopoiesis in human aging and disease

See allHide authors and affiliations

Science  01 Nov 2019:
Vol. 366, Issue 6465, eaan4673
DOI: 10.1126/science.aan4673

Figures

  • Somatic mutations, clonal hematopoiesis, and aging.

    Somatic mutations are acquired by all cells throughout life. Most are inconsequential, but rare mutations will lead to clonal expansion of hematopoietic stem cells (HSCs). If additional mutations are acquired, blood cancers may result. Emerging data also associate the presence of such clones with increased risk of cardiovascular disease (CVD) and death. Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.

  • Fig. 1 Mutational processes in aging.

    A single hematopoietic stem cell (HSC) in a healthy person acquires approximately one protein-coding mutation per decade of life (3). Four mutational processes contribute to the bulk of these age-associated mutations (right): spontaneous deamination of 5-methylcytosine to thymine, insertions and deletions (indels) caused by nonhomologous end-joining (NHEJ) of DNA double-strand breaks, errors in replication by DNA polymerase, and structural rearrangements of chromosomes, such as large insertions, deletions, and translocations. Assuming there are 50,000 to 200,000 HSCs in an average person (14), we estimate that by age 70, an average person without a hematological cancer will harbor 350,000 to 1.4 million protein coding mutations in his or her HSC pool. Shown at the bottom left is the expected number of random mutations (expressed as a range) 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 Prevalence of CHIP.

    The estimated prevalence of clonal hematopoiesis as a function of age varies according to the sequencing method used. Methods that are more sensitive, such as deep sequencing of select genes (34, 72, 73), will detect clonal hematopoiesis in more people than methods such as exome (28, 29) or genome sequencing (38), which typically have a much lower depth of coverage. The clinical consequences of clonal hematopoiesis are best understood for larger clones (>2% VAF). VAF, variant allele fraction; ECS, error corrected sequencing; WES, whole-exome sequencing; WGS, whole-genome sequencing.

  • Fig. 3 CHIP is associated with increased risk of acute myeloid leukemia and coronary heart disease.

    (A) Forest plots for risk of developing acute myeloid leukemia (AML) (72) and coronary heart disease (CHD) (80) in individuals with mutations in the genes listed. Only those mutations meeting the definition of CHIP were included. Individuals with mutations in more than one driver mutation are shown in the figure as a separate category (>1 driver gene). Lines represent the 95% confidence interval for odds or hazard ratios, and the sizes of the dots reflect the percentage of total CHIP mutations that are accounted for by each gene. (B) Hazard ratio (HR) and 95% confidence interval (CI) for developing CHD based on Framingham risk factors plus presence of CHIP mutations. Data are taken from population-based cohorts unselected for CHD status (29).

  • Fig. 4 Phenotypic changes in HSCs and immune cells with TET2 or DNMT3A mutations.

    HSCs that lack TET2 or DNMT3A display several convergent phenotypes in model systems, such as competitive advantage, enhanced self-renewal, myeloid bias in differentiation, and propensity for transformation to myeloid malignancies (5156). The mature immune effector cells that derive from these mutated HSCs are increasingly appreciated to be functionally altered as well. Recent work has found that loss of TET2 or DNMT3A increases inflammatory responses in macrophages (80, 87, 88, 93) and mast cells (95). Emerging work also suggests an effect of these mutations on T cell function, which may influence immune response to tumors (96, 97). CAR-T, chimeric antigen receptor T cell; GvH, graft-versus-host; BMT, bone marrow transplant.

Stay Connected to Science

Navigate This Article