PROJECT SUMMARY/ABSTRACT Myeloid malignancies comprise a heterogenous group of life-threatening clonal bone marrow neoplasms that affect over 150,000 people in the United States alone. Current treatment options for acute myeloid leukemia and myelodysplastic syndrome are limited, and have only modest benefits for high-risk patients. Deletion of part or all of chromosome 7 [-7/del(7q)] is a common cytogenetic change associated with adverse-risk prognosis and resistance to conventional therapies. The underlying genetic mechanism(s) in [-7/del(7q)] that leads to high- risk myeloid disease has remained a critical but unsolved question in the field. However, our lab has identified a tumor suppressor gene, CUX1, encoded on 7q that is recurrently mutated in myeloid disorders. CUX1 loss-of-function mutations are associated with a poor clinical prognosis independent of chromosome 7 cytogenetic abnormalities. Despite these findings, the endogenous role of CUX1 during hematopoiesis, and the mechanism by which it suppresses leukemia transformation, remain unclear, presenting a major barrier to understanding how CUX1 haploinsufficiency leads to high-risk disorders. My preliminary data suggest that CUX1 is required in human hematopoietic stem and progenitor cells (HSPCs) to suppress proliferation and promote erythroid development. Furthermore, my data indicate that CUX1 cooperates with the SWI/SNF nucleosome remodeling complex in HSPCs to regulate chromosome accessibility and promote erythroid gene expression. This proposal will utilize innovative functional genomic approaches, coupled with developmental assays with primary human HSPCs, to define the molecular and cellular mechanisms by which CUX1 regulates HSPC biology and differentiation. Fulfilling this gap in knowledge will be critical to aiding the development of new therapeutic strategies for high-risk myeloid malignancies. This proposal will also provide me with the expertise necessary to achieve my long-term goal of becoming an independent scientist in the field of cancer genomics. To oversee my project and career development, I have enlisted a team of highly qualified mentors with a breadth of experience in myeloid neoplasia, hematopoiesis, genomics, bioinformatics, and biostatistics. Together we have developed a robust training plan that incorporates individual and group meetings, didactic coursework, institutional resources and seminars, and attendance at international conferences to prepare me for a career in academic science.