As we age, we acquire somatic mutations in our hematopoietic stem cells (HSCs), some of which can confer a competitive advantage causing clonal HSC expansion. This clonal expansion is known as clonal hematopoiesis (CH) and is present in 10-15% of individuals aged 70 years or older. Individuals with CH have an increased risk of progression to hematologic malignancy compared to age-matched controls, as well as a higher risk of coronary heart disease and ischemic stroke. While CH can be detected using next-generation sequencing, this information is not sufficient to predict which individuals with CH will develop hematologic malignancy, coronary heart disease, ischemic stroke, or other complications. This prediction is currently not possible due to a lack of understanding of the mechanisms by which clonal HSC expansion and disease development occurs. The long-term goal of my work is to improve understanding of these mechanisms and discover interventions to stop or slow clonal HSC expansion and therefore decrease risk of CH-associated diseases in aging individuals. The novel approach that I am taking is to focus on alterations that occur during aging in context of the bone marrow (BM) microenvironment, which provides critical support for HSC function. To test the concept that CH is aging-associated because of changes occurring in the aged BM microenvironment, I will utilize an inducible mouse model of a hotspot mutation in the gene most frequently mutated in human CH, DNA methyltransferase 3A (DNMT3A). I hypothesize that a major source of selection pressure driving clonal HSC expansion is alterations in the aged BM microenvironment in which HSCs reside. I will test this hypothesis by evaluating the functional impact of changes in the BM microenvironment that have been previously described to occur generally with aging; altered cell type composition and increase in inflammatory cytokines, on expansion of Dnmt3a-mutant (Dnmt3amut) HSCs. I will determine cell type composition and differentiation potential of cells within young and old, Dnmt3amut and wild-type bones to identify cell type(s) and potential mechanisms driving Dnmt3amut HSC expansion in the aged BM microenvironment. Following this, I will functionally evaluate the effects candidate BM microenvironment cell types isolated from aged mice on Dnmt3amut and control HSCs using in vitro co-culture. Additionally, I will identify the cell type(s) in the BM that produce OSM, and perform ex vivo and in vivo studies inducing or inhibiting OSM signaling to assess Dnmt3amut HSC expansion. Successful completion of this project will determine the mechanisms by which, and extent to which, the aged BM microenvironment accelerates development of CH. Targeting these mechanisms has high potential to prevent or reduce clonal hematopoietic burden, and thus reduce incidence of hematologic malignancy, coronary heart disease, and ischemic stroke in aging populations.

Public Health Relevance

As the proportion of individuals ? 65 years old in the United States is expected to increase from 15% of the population in 2014 to 24% (~98 million individuals) by the year 2060, the overall incidence of clonal hematopoiesis (CH) is expected to increase significantly. Individuals with CH have a 10- to 15-fold increased risk of progression to hematologic malignancy compared to age-matched controls, as well as 2-fold higher risk of coronary heart disease and 2.6-fold higher risk of ischemic stroke. In the short term I will identify novel cellular and molecular mechanisms in the aged BM microenvironment that cause expansion of HSCs carrying a CH-associated mutation, in the long term this will aid in discovering new therapeutic targets to prevent CH and reduce incidence of hematologic disorders, coronary heart disease and ischemic stroke in aging populations.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDK1)
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Bishop, Terry Rogers
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Tufts University
Internal Medicine/Medicine
Schools of Medicine
United States
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