Wednesday, January 15, 2025
1/15/2025
ABSTRACT Blood diseases such as myelodysplastic syndromes (MDS) arise from hematopoietic stem cells (HSCs) that acquire genetic mutations which corrupt critical HSC functions. One of the most recurrently mutated genes in these neoplasms is the de novo DNA methyltransferase enzyme DNMT3A. However, DNMT3A mutations can occur in HSCs long before clinical presentation. Recent studies have shown that the HSC clones that predominate with age often contain mutations that are characteristic of myeloid neoplasms. This phenomenon is known as clonal hematopoiesis (CH), but only a small fraction of individuals with CH go on to develop a blood disease. This suggests that in addition to genetics, there must be other factors which act differently between individuals that select for propagation of HSCs with these mutations. Our lab is interested in identifying factors that change with age which may provide selective pressures for these mutant clones, focusing on inflammation. The prior funding period identified interferon gamma (IFNg) as an environmental stressor that selects for the outgrowth of Dnmt3a-mutant HSCs. While chronic IFNg signaling is detrimental to normal HSCs, functionality of Dnmt3a-mutant HSCs is preserved in this setting, presenting a mechanism whereby HSCs with these mutations gain clonal dominance in settings of inflammation. New data generated in our lab show that Dnmt3a-mutant HSCs are not only resistant to the detrimental effects of IFNg in vivo, but also the mutant clones produce more IFNg themselves in response to inflammation. This is associated with increased Cxcl9 expression from the mutant clones and T-cell infiltration into the BM. These observations form the scientific premise for this renewal application. We hypothesize that IFNg production by Dnmt3a-mutant clones suppresses other HSC genotypes and remodels the niche through T-cell infiltration to further reinforce their competitive advantage. We propose the following Specific Aims to investigate these questions; Determine if IFNg production from Dnmt3a-mutant clones exacerbates their competitive advantage. Determine if Dnmt3a-mutant clones remodel the BM niche. Examine the cellular and molecular mechanisms by which Dnmt3a-mutant cells are hypersensitive to IFNg. The overall goal of this work is to determine the mechanisms by which inflammatory signals promote clonal expansion of Dnmt3a-mutant HSCs in the bone marrow. Approaches to eliminate or selectively inhibit emerging DNMT3A-mutant HSC clones from high-risk CH+ individuals may provide a window for intervention before the mutant cells are able to establish clonal dominance and evolve to fulminant disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).