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Dr. Jaiswal's lab focuses on understanding the biology of the aging hematopoietic system. As a post-doctoral fellow, he identified a common, pre-malignant state for blood cancers by reanalysis of large sequencing datasets. This condition, termed "clonal hematopoiesis", is characterized by the presence of stem cell clones harboring certain somatic mutations, primarily in genes involved in epigenetic regulation of hematopoiesis. Clonal hematopoiesis is prevalent in the aging population and increases the risk of not only blood cancer, but also cardiovascular disease and overall mortality. Understanding the biology of these mutations and how they contribute to the development of cancer and other age-related diseases is the current focus of work in the lab. These studies utilize genetic and clinical information from large population-based cohorts to understand the impact of clonal hematopoiesis in humans. The effect of the mutations causing clonal hematopoiesis is also studied in human and mouse tissues through a combination of genomic profiling, functional assays, and mouse models of disease.
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.
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.
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.
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.
Somatic Mutations in Aging<br/><br/>Aging is associated with an increased incidence of cancer and several other diseases. As a post-doctoral fellow, Dr. Jaiswal 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). <br/><br/>The most commonly found mutations in CHIP are in genes involved in epigenetic regulation (DNMT3A, TET2, ASXL1). CHIP is very 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.<br/><br/>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.<br/><br/>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.