Aging of many tissues is accompanied by accumulation of mutations, which are thought to contribute to decline of tissue function. In the hematopoietic system, hematopoietic stem and progenitor cells (HSPCs) with somatic mutations have differential abilities to contribute to blood production, and over time, some of them exhibit enhanced contribution to the blood in a condition termed ?clonal hematopoiesis? (CH). Somatic mutations in CH are recurrently found in about 20 genes, but the mechanisms through which these mutations give particular clones an advantage are poorly understood. Mutations in PPM1D, which encodes a protein phosphatase that regulates stress and DNA damage responses, are found in about 5% of individuals with CH. CH-associated PPM1D mutations invariably truncate the protein and result in a hyperactive phosphatse. We hypothesize that hyperactive PPM1D provides an advantage to HSPCs via enhancing their survival after specific types of DNA damage. Here, we will focus on the behavior of PPM1D mutant HSPCs in a mouse model in the context of age and genotoxic stressors, and also examine the alterations in DNA repair pathways in PPM1D-mutant cells. First, we will examine clonal hematopoiesis in the context of aging and genotoxic stress in mice. Second, we will examine how mechanisms of DNA repair are altered in the context of PPM1D mutations. Overall, this study will expand our understanding of the mechanisms that give rise to clonal hematopoiesis, and in particular, the fitness landscapes and cellular mechanisms that promote clonal expansion, to establish a paradigm of context-specific clonal hematopoiesis. This insight will ultimately contribute to our understanding of the clinical implications and prognostic significance of clonal hematopoiesis.
Aging of many tissues is accompanied by accumulation of mutations (errors in the DNA), which are thought to contribute to decline of tissue function as we age. This phenomenon has been studied in the context of blood-forming stem cells and leads to the ability of some of these stem cells to outcompete the others, if they gain an advantage due to a specific kind of mutation. Sometimes these mutations also lead to cancer. Here, we are studying the relationship between mutations in one particular gene (PPM1D) to the effects of aging.
