Aging is associated with an increased incidence of cancer and several other diseases. We previously identified a common age-related disorder of the blood characterized by the acquisition of certain somatic mutations in hematopoietic stem cells (Jaiswal et al., NEJM 2014). These mutations allow stem cell clones to expand relative to normal stem cells; this clonal expansion is termed "clonal hematopoiesis of indeterminate potential", or CHIP (Steensma et al., Blood 2015).
The most commonly found mutations in CHIP are in genes that chemically modify DNA or chromatin to regulate transcription (DNMT3A, TET2, ASXL1). CHIP is rare in the young, but becomes common with aging. Between 10-30% of the elderly have a clonal mutation meeting the definition of CHIP. Those with CHIP are at markedly increased risk of developing hematological malignancies such as myelodysplastic syndrome, acute myeloid leukemia, and lymphoma.
Surprisingly, CHIP is also associated with increased risk of atherosclerotic cardiovascular disease, and this relationship is thought to be causal based on mouse models (Jaiswal et al., NEJM 2017). Mechanistically, the mutations in CHIP lead to increased expression of inflammatory gene modules in mature immune cells such as macrophages. These immune effector cells are derived from the mutated hematopoietic stem cells in the marrow, hence they also harbor the CHIP-related mutations.
These observations suggest that somatic mutations in hematopoietic stem cells that arise during aging may have a variety of effects on health. The lab seeks to understand the biology and clinical impact of these mutations, as described in the projects below.
USING HUMAN POPULATION GENETICS TO LEARN THE HEALTH ASSOCIATIONS OF CLONAL HEMATOPOIESIS.
Chronic inflammation seems to be a common feature of human aging, but the reasons for this are unclear. We hypothesize that CHIP might actually underlie much of the age-associated inflammation seen in humans. Consequently, CHIP might modulate the risk of several diseases of aging.
MECHANISTIC STUDIES ON THE ROLE OF DNA METHYLATION IN CLONAL EXPANSION OF STEM CELLS AND DYSREGULATED INFLAMMATION.
It is striking that the two most frequently mutated genes in CHIP, DNMT3A and TET2, are involved in DNA methylation dynamics. We hypothesize that these mutations lead to alterations in DNA methylation that promote self-renewal and inflammatory transcriptional programs. Using model systems, we will uncover the role of methylation in these programs.
CHARACTERIZATION OF HEMATOPOIETIC AND IMMUNE CELL SUBSETS FROM HUMANS WITH CHIP.
Much of our knowledge of the effects of mutations found in CHIP comes from mouse models because individuals with CHIP do not have overt disease, hence they do not enroll in clinical studies. We seek to prospectively identify individuals with CHIP to learn more about how these mutations affect stem cell and immune cell function in a native human context.
Identification of novel therapeutics to treat CHIP and/or its associated diseases.
If CHIP mutations lead to aberrant stem cell and immune cell function by altering gene expression, it should be possible to reverse these effects therapeutically. We aim to identify suitable targets for intervention to prevent stem cell expansion and inflammation associated with CHIP.