The triggering events and cell of origin for leukemia development are usually unknown. We have recently discovered a novel mouse model of B cell leukemia, in which the Notch mediator RBP-J is deleted within renin- expressing cells. We found that the cell of origin for this model is a B lymphocyte progenitor which expresses renin and experiences malignant transformation upon RBP-J deletion. In this project, we propose to further study renin expression during normal and neoplastic hematopoiesis. We hypothesize that renin-expressing hematopoietic cells represent a primitive component of the hematopoietic system with differential transformative capacity and that RBP-J is necessary for appropriate regulation of these cells. Using in vivo lineage tracing, time and cell specific conditional deletin approaches, gene-expression profiling, and immunophenotyping, we propose to further investigate this novel progenitor cell, including its expression patterns during hematopoietic ontogeny, its contribution to differentiation of hematopoietic organs, and its influence on leukemia development. First, we will study the temporal appearance and identity of renin- expressing cells within hematopoietic organs during embryonic and post-natal life. Second, we will delete RBP-J in renin-expressing cells at specific developmental stages to determine when RBP-J becomes critical to normal development of these cells. Third, we will directly compare the malignant potential of B cell subsets by deletion RBP-J in distinct population of B cells using cell-specific deletion. Dr. Belyea's professional goals are to conduct meaningful bench research that will advance the fields of hematopoiesis and leukemogenesis and ultimately improve the cure rate of childhood cancers. He is supported by an experienced and successful mentoring committee that will provide strategic expertise on embryonic development, hematopoiesis, and lymphocyte development. Dr. Belyea has demonstrated commitment to research by pursuing bench research at multiple steps of his career (undergraduate, medical school, fellowship), having a successful (early) publication record, and generating exciting preliminary data. His career development plan is guided by his primary mentor, Dr. Ariel Gomez, an exceptional scientist, experienced advisor, and a leader in developmental biology. This project and his career development plan will provide the foundation for a successful career as an independent investigator and leader in the field of embryonic origins of childhood cancers.
B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer and is believed to arise when a susceptible cell of origin undergoes a genetic mutation. However, the precise triggering events and the cell of origin for leukemia development are usually unknown. An improved understanding of leukemia pathogenesis will allow for improved diagnosis, surveillance, and the development of rational treatment strategies. By providing new and fundamental knowledge regarding the cell of origin and driving mechanisms of leukemia development, this proposal has the potential to benefit children and adults with hematopoietic malignancies.