Inflammatory Disease Associations in Clonal Hematopoiesis

Project Summary Clonal hematopoiesis (CH) is the pre-malignant expansion of a population of blood cells derived from a single hematopoietic stem cell and is often caused by somatic mutations in leukemia driver genes. CH has been associated with significant clinical outcomes including hematologic cancers, various inflammatory comorbidities, and increased all-cause mortality. Among individuals with CH, there is inconsistent penetrance for inflammatory disease symptoms and risk of inflammatory disease varies widely. Reliable clinically-validated models that estimate a patient’s risk of inflammatory disease outcomes and management strategies that prevent or effectively overcome inflammatory disease outcomes in CH are major medical needs. The goal of this proposal is to define and better understand the relationship between CH and inflammatory disease outcomes. Aim 1 will define the association between CH and rheumatologic diseases and activities in Aim 2 will define the CH genotypes most powerfully linked to inflammatory phenotypes and generate a statistical algorithm to estimate individual risk of inflammatory disease in patients with CH. Then, using a cohort of patients with clonal cytopenia of uncertain significant (CCUS), a subtype of CH, who have been exposed to hypomethylating agents (HMA), Aim 3 will explore the influence of HMA therapy on inflammatory disease symptoms. Collectively, this work will enable the identification of patients with CH who are at risk for inflammatory diseases and provide preliminary data to motivate future interventional clinical trials with endpoints designed around prevention of inflammatory disease outcomes. Dr. Lachelle D. Weeks is a hematologist and scientist at the Dana-Farber Cancer Institute (DFCI) and translational investigator in the Division of Population Sciences within the Department of Medical Oncology at DFCI. She spends 80% of her time in translational research and 20% in clinical practice caring for and counseling patients with CH and myelodysplastic syndrome (MDS). In addition to her primary mentor, Dr. Weeks has established an advisory committee of internationally recognized experts in CH, myeloid malignancies, clinical computational oncology, and genetic epidemiology. Her research and career development activities will be conducted at DFCI which has an outstanding research community and a long track record for successful mentorship of independent scientists. This is an ideal environment for completion of the proposed research, execution of the proposed career development strategy, and the ultimate realization of Dr. Weeks’s long-term career goal of becoming an R01-funded physician-scientist.