Determinants of Myeloid Clonal Evolution

PROJECT ABSTRACT Clonal hematopoiesis is acquired with aging, and in some cases, precedes the onset of both myelodysplastic and myeloproliferative disorders. However, the genetic drivers that underlie the evolution of clonal hematopoiesis and the subsequent disease risk remain poorly understood. This proposal builds on generated evidence showing that telomere length, a genetic and clinically available biomarker, predisposes to clonal hematopoiesis in Mendelian syndromes. We have also found evidence for distinct clonal hematopoiesis mutations that appear to differentially predispose to hypoplastic and myeloproliferative phenotypes. In this application, we will examine the role of telomere length in driving clonal evolution with aging in well- characterized cohorts including a Baltimore-based cohort of community-based women with a large African American subset. Additionally, we will also examine the onset and prevalence of a novel clonal hematopoiesis mutation in the telomerase reverse transcriptase gene that appears to be protective against myeloid malignancies. This K08 grant application is supported by outstanding mentors and in a strong translational environment at Johns Hopkins University School of Medicine with a detailed mentorship and training plan that focuses on genetic epidemiology and computational biology skills. The knowledge has the potential to impact current paradigms related to hematopoietic aging, myeloid clonal disease risk as well as novel biomarkers of specific disease risk and progression.