Early Clonal Evolution in Acquired Aplastic Anemia

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PROJECT SUMMARY/ABSTRACT This K08 Career Development Award proposal describes the candidate’s 5-year training program to become an independent physician-scientist in academic hematology, with a focus on bone marrow failure syndromes. The Principal Investigator (PI) has completed M.D. and Ph.D. Degrees at the University of Pennsylvania (Penn), followed by residency training in Internal Medicine at the Massachusetts General Hospital, fellowship training in Hematology-Oncology at Penn, and is currently an Assistant Professor in Medicine at the University of Pennsylvania. Through the 5-year career development plan of the parent K08 award, the PI will expand her knowledge and research skills in hematopoiesis, stem cell biology, and immunology in order to develop an independent research program studying clonal hematopoiesis in acquired aplastic anemia (aAA). The PI will be mentored by Dr. Peter Klein, an expert on hematopoiesis, as well as the Advisory Committee, who will foster PI’s scientific and career development. The proposed research focuses on aAA, a life-threatening blood disease affecting children and adults caused by immune destruction of early hematopoietic cells. Clonal evolution to leukemia is a common complication, with no effective prevention strategy available. Emerging data indicate that up to a quarter of aAA patients acquire somatic mutations and may be at a greater risk of malignant transformation. Therefore, understanding clonal hematopoiesis in aAA is important to allow for early detection and improved therapies. The objective of the K08 award is to characterize the full spectrum of clonal hematopoiesis in aAA and to dissect the mechanisms driving emergence of clones. This will be accomplished in three specific aims: 1) Characterize the landscape and prevalence of somatic mutations in the bone marrow of aAA patients using an unbiased genetic analysis, 2) Identify genomic biomarkers of response to therapy and disease outcomes, and 3) Characterize the function of candidate driver mutations in hematopoiesis. The successful completion of this project is expected to have a sustained and lasting impact in the field by providing an understanding of clinically relevant somatic alterations in aAA, which could serve as genetic biomarkers and targets for new personalized therapies. The strong scientific expertise and the mentorship track record of the PI’s Mentor and Advisory Committee, together with the unique resources and outstanding research facilities at Penn, make this an ideal environment for this K08 Award. This research program, performed in the context of a comprehensive career development plan, will support the PI’s career transition to become an independent physician-scientist in Hematology.