Developing Effective Approaches to Extend Hematopoietic Healthspan by Targeting Cell-Extrinsic and Cell-Intrinsic Alterations at Middle Age

Jackson Laboratory, Bar Harbor ME

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Abstract

Aging is associated with clonal hematopoiesis (CH), a poorly understood process by which long-lived hematopoietic stem cells (HSCs) and their progeny with certain somatic mutations undergo positive selection. Individuals with CH have increased risk of developing blood cancer, cardiovascular disease, type 2 diabetes, and all-cause mortality. Understanding how and why CH occurs with aging, and defining effective interventions to extend healthspan, have strong potential to reduce CH-associated diseases in aged individuals. Using a mouse model of a common CH mutation in DNMT3A, we have made a novel discovery that Dnmt3a-mutant HSCs induce senescence of stromal cells in the bone marrow (BM) microenvironment. Further, we found that administering a Bcl2/BclxL-targeting senolytic drug to Dnmt3a-mutant mice was sufficient to reduce the selective advantage of Dnmt3a-HSCs in vivo. In Aim 1, we will determine the specific cytokines and growth factors produced by Dnmt3a-mutant HSCs that have the capacity to induce senescence of BM stromal cells ex vivo. In Aim 2, we will determine the extent to which Dnmt3a-mutant HSCs themselves are sensitive to Bcl2/BclxL-targeting senolytic drugs. Successful completion of this project will begin to refine our understanding of the mechanism(s) by which Dnmt3a-mutant HSCs modify their microenvironment and define the cell type(s) impacted by senolytic drugs to limit CH.