PROJECT SUMMARY/ABSTRACT There are currently an estimated 15.5 million cancer survivors in the U.S., and this number is expected to surpass 20 million in the next ten years. The current standard of care for most cancer patients includes treatment with ionizing radiation and/or chemotherapeutic agents. An unintended, and devastating, late-effect of successful cytotoxic therapy is the development of therapy-related myeloid neoplasms (t-MNs) in a subset of patients. With the number of cancer survivors in the U.S. on the rise, the number of patients presenting with t- MN is expected to rise as well. T-MN is associated with a dismal prognosis, comorbidities, and high-risk cytogenetic abnormalities. The most common cytogenetic change in t-MN is the loss of chromosome 7 (-7) or the long arm, [del(7q)], which is found in half of all cases of t-MN. How -7/del(7q) drives the pathogenesis of t- MN remains a crucial question in the field. Our lab has discovered a haploinsufficient myeloid tumor suppressor gene encoded on 7q, CUX1. CUX1 is a homeobox transcription factor previously shown to regulate cell proliferation, stem cell quiescence and apoptosis. No mouse model currently exists for -7/del(7q)-driven t-MN. As this cytogenetic abnormality is both the most common in t-MN and associated with a poor prognosis, this is an especially pressing problem. Our lab has developed doxycycline-inducible shRNA CUX1-knockdown mouse models to understand the role of CUX1 in the pathogenesis of t-MN. My preliminary data has shown that CUX1-knockdown mice develop a block in erythropoiesis and anemia, splenomegaly, a myelomonocytic expansion and rapidly become moribund within four months of treatment. Colony forming unit assays have shown that CUX1 deficiency leads to an increase in HSPC proliferation, as well as lineage skewing towards the granulocyte/monocyte lineage at the expense of lymphoid development and erythropoiesis. Our studies suggest that CUX1 deficiency plays a key role in the pathogenesis of t-MN, specifically by driving clonal hematopoiesis, promoting PI3K/Akt signaling and deregulating proliferation and survival. This proposal aims to (i) determine the mechanism of the clonal expansion of CUX1-deficient cells in response to chemotherapy and (ii) understand the changes in chromatin accessibility and transcriptional regulation of proliferation and survival that occur in a CUX1-deficient state. T- MNs are aggressive, resistant to treatment and carry a poor prognosis. Understanding the pathogenesis of these diseases will lead to the development of better strategies to treat the subset of cancer survivors that develop t-MN. The project that I propose here will leverage the expertise of my mentors and advisory committee in the fields of therapy-related myeloid neoplasms and cancer cytogenetics to create a comprehensive, vertically-integrated graduate training experience that will propel me towards becoming an successful independent physician-scientist.