Deletions of chromosome 5 centering at 5q31 occur frequently in aggressive myeloid malignancies, including therapy-related leukemia, acute leukemia and myeloidysplastic syndrome. These deletions are among the worst prognostic indicators, as they are associated with multilineage involvement, rapid progression to acute leukemia, primary resistance to chemotherapy, and short survival. In contrast, such deletions are infrequent in non-myeloid cancers or solid tumors. The investigators' recent progress in preparing a physical map of 5q31, and their analysis of deletions in clinical material has enabled them to specify a small segment that is involved in all cases regardless of deletion extent. This commonly deleted segment is contained within an interval of approximately 1 to 1.5 Mb, specified by the markers IL9-D5S414. The investigators propose that this interval is the site of a myeloid-specific tumor suppressor gene, and the overall objective of this proposal is to identify this gene.
The specific aims are: (1) to complete the physical map of the deletion interval, including a P1/BAC contig and an expressed sequence map; (2) to evaluate genes and expressed sequences which lie within the interval as candidates for the tumor suppressor gene; (3) to identify the gene, and begin to characterize its biologic activity and its clinical relevance. Since the last submission of this R01, the physical map/P1 contig is almost complete, the investigators have identified 12 candidate expressed sequences, and have begun detailed testing of these candidate genes. Thus, they feel that they are in a good position to achieve their goals. The recent move of the Westbrook laboratory to UIC will strengthen this project considerably, as they enlist the aid of new collaborators with a large clinical program in AML and MDS, and investigators with expertise in hematopoiesis, who will contribute to their efforts to identify the gene, and to develop model systems in which to study its function and its role in malignant myeloid transformation.
