Friday, May 9, 2025
5/9/2025
Interrogating the Clonal Architecture of Human Hematopoiesis by Mitochondrial Lineage Tracing - Project Summary During aging, human hematopoietic stem cells decline in function, with consequences including cytopenias, increased risk of blood cancer, and decreased regenerative capacity.1–3 Along with other intrinsic and extrinsic changes, somatic mutations that accumulate in individual stem cells have been recognized as a major contributor this process.4,5 Some of these mutations convey fitness advantages, resulting in clonal expansion; this phenomenon, termed clonal hematopoiesis, is present in the majority of people past the age of seventy, and has been associated with increased risk of blood cancer and cardiovascular disease, partially attributed to a pro-inflammatory cellular environment.2,6–8 Along with somatic variation driving clonal expansion, high-penetrance inherited genetic variants also cause impactful changes to the clonal composition of hematopoietic stem cells during the lifespan. Interestingly, rare inherited Mendelian mutations in RUNX1 which cause RUNX1 Familial Platelet Disorder are associated with an extremely high incidence of clonal hematopoiesis and overt leukemia.9–13 To date, the interplay between these germline and somatic mutations driving HSC clonal expansion and the pro-inflammatory microenvironment in which the clones expand is not fully understood, nor is it known how these changes collectively drive the functional decline and increased morbidity associated with clonal hematopoiesis in humans.14 In this grant, I propose to map the disruption of the clonal architecture of human hematopoietic stem cells driven by high-effect somatic and germline variants, and identify the phenotypic changes by which this results in impaired stem cell function and increased disease risk with aging. Aim 1 proposes to extend the mitochondrial lineage tracing methodology we have developed in the Sankaran laboratory to call nuclear DNA variants. Aim 2 will use these methods to define at high resolution the changes in the overall clonal architecture observed during human aging, and identify the causative interactions between inflammatory signaling, somatic mutations, and clonal expansions in hematopoietic stem cells during aging. Aim 3 will examine the alterations to hematopoietic clonal structure caused by RUNX1 germline mutations, and how these alterations contribute to the observed hematopoietic dysfunction and increased leukemia risk observed in RUNX1 Familial Platelet Disorder. These studies will reveal mechanistic insights into how hematopoietic clonal structure changes across the lifespan and the consequences for hematological function and disease.
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