Therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) are distinct clinical syndromes that have been recognized as late complications of cytotoxic therapy (either radiation and/or chemotherapy) used in the treatment of both malignant and nonmalignant diseases. We reported previously that nonrandom chromosomal abnormalities are commonly observed in the malignant cells of patients with t-MDS/t-AML. In our updated series, we observed loss of an entire chromosome 5 and/or 7 or a deletion of the long arm of these chromosomes [del(5q)/del(7q)] in 97 of 129 (75%) patients whom we examined. By comparing the deletions of chromosome 5 observed in these patients, we have determined that a small region (critical region), consisting of band 5q31, is consistently deleted in all patients, suggesting that loss of a gene(s) located within this segment is involved in the pathogenesis of these myeloid disorders. Of note is the fact that this region contains the genes encoding four hematopoietic growth factors; however, no direct role for these genes in myeloid leukemogenesis has been demonstrated. We now propose to use cytogenetic and molecular approaches to map the critical region of 5q by using in situ chromosomal hybridization and radiolabeled or biotin-labeled probes, and physical mapping techniques, such as pulsed-field gel electrophoresis (performed in collaboration with Dr. Carol Westbrook). Similarly, cytogenetic analysis of patients who have t-MDS/t-AML with deletions or other rearrangements of 7q and gene mapping techniques will be used to prepare a genetic map of the critical region of chromosome 7. To determine if DNA rearrangements have occurred within the critical region of the normal 5 homologue, we will then use this map to examine DNA derived from leukemia cells of t-AML patients with a del(5q) or other rearrangements of 5q, and from t-AML patients who do not have a cytogenetic abnormality of 5q. The detection of DNA rearrangements will identify candidate """"""""suppressor"""""""" genes that may be integrally involved in leukemogenesis.
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