) Loss of chromosome 7 (monosomy 7) and deletion of a segment of the long arm (del(7q)) are recurring cytogenetic abnormalities that are strongly associated with secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as with cases of MDS and AML that arise in a number of other contexts including occupational exposure to mutagens, aplastic anemia, and certain inherited predispositions. Monosomy 7 and del(7q) frequently coexist with molecular alterations of the Ras signaling pathway in MDS/AML clones. The similar clinical and biologic features of patients with different antecedent risk factors implicate alterations of the same gene on 7q in the pathogenesis of all of these myeloid disorders. Cytogenetic and FISH analysis have been utilized to delineate two commonly deleted segments in patients with myeloid disorders characterized by a del(7q): one located in band q22 that accounts for most cases and a second segment in bands q32-33. These data are consistent with the hypothesis that recessive mutations which inactivate tumor suppressor genes within these commonly deleted segments contribute to leukemogenesis in patients with monosomy 7 or del(7q). The goal of this project is to identify and characterize the putative tumor-suppressor gene located on 7q22. Dr. Le Beau and her colleagues (Project 3) will employ cytogenetic techniques to narrow the commonly deleted segment on band q22 and we will utilize polymorphic markers that map within the critical region to investigate patient samples for submicroscopic deletions. We will use genomic DNA from the commonly deleted segment that is cloned in yeast artificial chromosomes and bacterial artificial chromosomes as probes for screening CDNA libraries and will also employ exon trapping and subtractive hybridization approaches to isolate new coding sequences that map within the commonly deleted segment. Finally, we will analyze bone marrow samples from patients with monosomy 7 or del(7q) for mutations in candidate genes that are identified by these approaches. This work will be facilitated by the large and diverse collection of specimens from adults and children with monosomy 7 and del(7q) maintained in our laboratory and at the University of Chicago, by a close interaction with Dr. Le Beau (Project 3), and by a collaboration with Dr. Eric Green whose laboratory is constructing a physical map of chromosome 7.
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