Why do some people get cancer and others do not gets to the heart of cancer biology. Recently, the NCI invited leading cancer investigators to identify provocative questions that will transform our understanding and treatment of cancer. Our application addresses one of these questions: are there definable properties of premalignant lesions that predict the likelihood of progression. This is not just of profound biological importance, but also of great relevance to people with cancer predisposition. Patients with congenital bone marrow failure syndromes (for example, Fanconi anemia, Shwachman-Diamond Syndrome, Severe Congenital Neuropenia, and dyskeratosis congenital) are at greatly increased risk (1000x) for developing life-threatening acute myeloid leukemia/myelodysplastic syndromes (AML/MDS). What are the genetic factors that contribute to disease progression? Can this progression be prevented first by identification of these genetic co-modifiers and then to design preventative measures? This proposal seeks to identify genetic co-modifiers that arise in patients with Shwachman-Diamond Syndrome, one of the more common inherited bone marrow failure syndromes with the risk of AML/MDS. However, two major obstacles block progression: the low prevalence of the disease and the decade long latency period. To overcome these obstacles we are developing an adult zebrafish model of Shwachman-Diamond Syndrome and screen for genetic mutations that result in leukemia. The disease is due to a mutation in the SBDS gene, which encodes a protein involved in ribosomal maturation. We have cloned the highly homologous zebrafish gene, sbds, and its promoter for the sbds gene and have developed tools for controlled expressions of Sbds. Fascinatingly, almost all patients with this syndrome who develop leukemia acquire loss of chromosome 7. This abnormality is also found in a number of pediatric and adult patients with AML/MDS. While there is a minimally deleted region on chromosome 7q, the identity of that tumor suppressor is unknown. We will test several candidate genes in our model system. By identifying genetic co-modifiers and determining how they disturb hematopoiesis, we will be able to eventually design preventative strategies as well as more effective therapies for those who have already developed AML/MDS. In addition, since Shwachman-Diamond Syndrome also causes pancreatic insufficiency, growth retardation, and developmental disabilities, our model will have added value to other biologists and clinicians.