Clonal hematopoiesis, somatic mosaicism, and age-associated disease

Abstract

Somatic mosaicism, the occurrence of multiple genetically distinct cell clones within the same tissue, is an evitable consequence of human aging. The hematopoietic system is no exception to this, where studies have revealed the presence of expanded blood cell clones carrying mutations in preleukemic driver genes and/or genetic alterations in chromosomes. This phenomenon is referred to as clonal hematopoiesis and is remarkably prevalent in elderly individuals. While clonal hematopoiesis represents an early step toward a hematological malignancy, most individuals will never develop blood cancer. Somewhat unexpectedly, epidemiological studies have found that clonal hematopoiesis is associated with an increase in the risk of all-cause mortality and age-related disease, particularly in the cardiovascular system. Studies using murine models of clonal hematopoiesis have begun to shed light on this relationship, suggesting that driver mutations in mature blood cells can causally contribute to aging and disease by augmenting inflammatory processes. Here we provide an up-to-date review of clonal hematopoiesis within the context of somatic mosaicism and aging and describe recent epidemiological studies that have reported associations with age-related disease. We will also discuss the experimental studies that have provided important mechanistic insight into how driver mutations promote age-related disease and how this knowledge could be leveraged to treat individuals with clonal hematopoiesis.

Keywords: age-related clonal hematopoiesis; clonal hematopoiesis of indeterminate potential (CHIP); inflammaging; mosaic chromosomal alterations; therapy-related clonal hematopoiesis.

Graphical abstract

FIGURE 1.

Summary of some of the organs where somatic mosaicism has been documented.

FIGURE 2.

Simplistic summary of types of mutations observed in age-related clonal hematopoiesis. Created with BioRender.com, with permission. HSCs, hematopoietic stem cells; mCAs, mosaic chromosomal alterations; mLOY, mosaic loss of the Y chromosome. Diagram adapted from Ref. , with permission from Nature Reviews Genetics.

FIGURE 3.

The prevalence of clonal hematopoiesis depends on the sequencing approach and limit of detection. Less sensitive methods, such as whole exome sequencing restricted to candidate driver genes, estimate a lower prevalence of clonal hematopoiesis. Highly sensitive techniques, such as error-corrected sequencing, predict that clonal hematopoiesis is much more prevalent. DNMT3A, DNA methyltransferase 3A; TET2, ten eleven translocation 2; VAF, variant allele frequency.

FIGURE 4.

Simplistic overview of therapy-related clonal hematopoiesis. Hematopoietic stem cells (HSCs) with mutations in DNA-damage response (DDR) genes, such as tumor suppressor protein 53 (TP53) or protein phosphatase Mn²⁺/Mg²+-dependent 1D (PPM1D), are present in very small numbers in normal bone marrow. Upon exposure to chemotherapy and/or radiation during treatment for cancer, clones with mutations in DDR genes have a survival advantage. Over time with each successive exposure, the mutant cells with the survival advantage become selected for within the bone marrow, thereby facilitating their clonal expansion. Created with BioRender.com, with permission.

FIGURE 5.

Diagram summarizing documented associations between driver gene-mediated clonal hematopoiesis and human disease. Created with BioRender.com, with permission. COPD, chronic obstructive pulmonary disease.

FIGURE 6.

Diagram summarizing documented associations between mosaic chromosomal alterations (mCAs) of autosomes, including mosaic loss of the Y chromosome (mLOY), and human disease. Created with BioRender.com, with permission.

FIGURE 7.

Summary of experimental work causally linking clonal hematopoiesis with disease. Each disease is listed alongside the specific mutation that was investigated. Created with BioRender.com, with permission. BM, bone marrow; BMT, bone marrow transplant; Tet2, ten eleven translocation 2; Dnmt3a, DNA methyltransferase 3a; mLOY, mosaic loss of Y chromosome; Jak2, janus kinase 2; Ppm1d, protein phosphatase, Mg²⁺/Mn²⁺ dependent 1d; Trp53, transformation related protein 53.

FIGURE 8.

Overview of mouse models of clonal hematopoiesis. Top: mouse models that have been previously used to study clonal hematopoiesis. Bottom: potential sources of mutant murine bone marrow cells that can be used to create the mouse models. Created with BioRender.com, with permission. Tet2, ten eleven translocation 2; Jak2, janus kinase 2; BM, bone marrow; BMT, bone marrow transplant.

FIGURE 9.

Summary of the work mechanistically linking ten eleven translocation 2 (TET2)-mediated clonal hematopoiesis to augmented IL-1β signaling. Top: Tet2 deficiency in macrophages leads to an increase in IL-1β transcription as well as increased expression of the NLRP3 inflammasome. As a result of these transcriptional changes, Tet2-deficient macrophages produce higher amounts of active IL-1β. Bottom left: blocking IL-1β production by inhibiting the NLRP3 inflammasome has been shown to reduce the burden of atherosclerosis, heart failure, and metabolic disease in mouse models of Tet2-mediated clonal hematopoiesis. Bottom right: in a subanalysis of the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) it was found that individuals with hematopoietic mutations in TET2 experienced a substantially greater reduction in major adverse events than individuals without clonal hematopoiesis of indeterminate potential (CHIP) following treatment with the IL-1β neutralizing antibody Canakinumab. Created with BioRender.com, with permission. MACE, major adverse cardiovascular events.

FIGURE 10.

Summary of experimental work linking hematopoietic mosaic Y chromosome loss (mLOY) to cardiac fibrosis. Following injury, leukocytes migrate from the bone marrow to the heart and are involved in the pathogenic pathways leading to heart failure. Under mLOY conditions, blood-derived macrophages adopt a more fibrotic phenotype characterized by an enrichment of genes involved in transforming growth factor-1β (TGF-β1) signaling. Consequently, this leads to an elevation in cardiac fibroblasts and matrix deposition thereby augmenting cardiac fibrosis. Created with BioRender.com, with permission. HSC, hematopoietic stem cells; TAC, transverse aortic constriction.