Each year, in the U.S. alone, over 50,000 people are diagnosed with myeloid cancers of the blood. Some myeloid cancers have been found to lose all or a portion of chromosome 7 [-7/del(7q)], and these cases are particularly difficult to treat. The overall survival for these patients is less than one year. -7/del(7q) also occurs in half of therapy-related myeloid neoplasms/cancers (t-MN). t-MN arise as a side effect of chemotherapy/radiation and occur in u to 8% of cancer survivors. There is clearly an urgent need to develop better therapies for -7/del(7q) disease. It has long been thought that one or more genes on chromosome 7 prevents cancer growth – “tumor suppressor genes.” I used genomic technologies and animal models to map this tumor suppressor gene, implicating CUX1. The long-term goal of the current proposal is to improve the outcome for patients with this type of disease. This proposal is designed to accomplish this by identifying CUX1-regulated pathways that may be potential drug targets as well as establish animal models for future use in preclinical therapy development. The contribution of the proposed research is expected to bhe characterization of the biological outcomes and altered pathways caused by CUX1 loss–the first step toward developing therapies. The significance of this work is not limited to leukemia; CUX1 is mutated in endrometial cancer, gastric cancer, and melanoma, among other tumors. Thus, the understanding of CUX1 function in myeloid disease may guide our knowledge of the role of CUX1 in other cancers.