The impact of increased mutation burden on promoting clonal hematopoiesis

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PROJECT SUMMARY/ABSTRACT Somatic mutations occur in hematopoietic stem cells (HSCs) throughout life. By chance, a mutation may disrupt a key gene and confer a competitive advantage on the mutant HSC, leading to expansion of its clonal progeny. This phenomenon is called clonal hematopoiesis (CH) and is ubiquitous with increasing age. CH is associated with elevated risk for hematological malignancy, cardiovascular and pulmonary diseases, type II diabetes, and overall all-cause mortality. Nearly all adults older than 50 years harbor CH clones with mutations in leukemia- associated genes, but these mutant clones comprise a very low fraction of total blood cells and thus are speculated to be functionally inert. A growing body of literature indicates that, in most individuals, low-frequency mutant clonal blood fractions remain stable over time. However, no models exist that capture the behavior of these stochastically arising low-frequency clones. Thus, whether driver mutation acquisition and adequate time will lead to eventual clonal expansion remains unknown. The goal of this proposal is to determine the extent to which underlying HSC mutation burden and acquisition of CH drivers are sufficient for clonal expansion over time. Preliminary calculations predict every coding gene is mutated about 70 times in the HSC pool during an average human lifespan, indicating mutation in a CH driver gene is inevitable with longevity. In contrast, native CH has never been reported in murine models, possibly because mice have fewer HSCs and a limited lifespan during which to acquire HSC mutations. The central hypothesis of this proposal is that clonal hematopoiesis emergence is the product of sufficient mutation rate and time. I will evaluate this hypothesis using two murine models for stochastic mutation acquisition. Experiments proposed in Aim 1 will query aged wild-type mice to determine the extent that advanced age, independent of lifespan, promotes the development of CH. In Aim 2, I will experimentally elevate the global mutation burden in murine HSCs to determine if the stochastic acquisition of a CH driver mutation will lead to mutant clonal expansion over time, and how an aged milieu impacts CH development. The experiments will define the sufficiency of mutation burden and time for promoting clonal hematopoiesis and will determine the role of an aged microenvironment in clonal expansion. Overall, this work may uncover strategies to enhance healthy aging via modulation of mutant clonal outgrowth.