Delineating Drivers of Inflammation and Progression in Clonal Hematopoiesis

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(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Somatic, leukemia-associated mutations commonly occur in hematopoietic stem and progenitor cells (HSPC) during aging in the absence of hematologic malignancy. Cells harboring these mutations exert stress on the bone marrow microenvironment, disrupting normal hematopoiesis, both with respect to stem cell intrinsic changes and microenvironmental perturbations, leading to clonal expansion, bone marrow failure, and risk of malignancy. However, only a fraction of individuals with CHIP progress to significant bone marrow disruption and understanding which individuals will progress remains a significant gap in the field. Using a systems hematology approach, we propose a course of study to identify factors that contribute to clonal expansion and disease progression in human CHIP. Our long-term goal is to dissect the pathogenic mechanisms of clonal myeloid disorders and identify therapeutic targets to reverse disease progression. Inflammation has a well-known association with mTET2 CHIP, but the immune effects in humans and causes at the epigenetic levels have not been elucidated. This bridge funding will allow us to optimize our approach to imputing genotype onto transcriptional single cell data. It will expand our effort to characterize the epigenetic responses to TET2 loss and identify mechanistic changes that precipitate a disrupted immune microenvironment. Ultimately, this will directly strengthen our next submission of this work as an expanded research project grant.