Therapy-related acute nonlymphocytic leukemia (t-ANLL), a distinct clinical syndrome, has been recognized as a late complication of cytotoxic therapy (either radiation and/or chemotherapy) used in the treatment of both malignant and non-malignant disease. We reported previously that nonrandom chromosomal abnormalities are commonly observed in the malignant cells of patients with t-ANLL. Specifically, 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)) occurs in 55 of 63 (87%) patients whom we examined. By comparing the deletions of chromosome 5 observed in these patients, we determined that a small region (critical region), consisting of bands 5q23 and q31, was consistently deleted in all patients, suggesting that loss of genes located within this segment is involved in the pathogenesis of myeloid disorders characterized by a del (5q). More recently, we have mapped the genes encoding three myeloid_ specific growth factors-and the receptor for one of these factors within or adjacent to the critical region of 5q--and have shown that these genes are deleted in the bone marrow cells of patients with a del (5q). We no propose to use molecular approaches to examine the potential role of these genes or to identify and isolate the gene(s) within the critical region of 5q, whose altered function as a result of recessive mutations, such as chromosomal or submicroscopic deletions, plays a role in the pathogenesis of myeloid disorders. The initial step will be to prepare a physical linkage map of genes and anonymous DNA sequences within the critical region of 5q by using in situ chromosomal hybridization and physical mapping techniques, such as pulsed- field gel electrophoresis. We will then use this map to examine DNA derived from t-ANLL patients with a del (5q) and t-ANLL patients who do not have a cytogenetic abnormality of 5q to determine if DNA rearrangements have occurred within the critical region of the normal 5 homologue. In addition, we will use differential cDNA screening techniques to identify genes that are normally expressed in myeloid cells but whose expression is absent in cells obtained from leukemia patients with a del(5q), thereby identifying candidate """"""""suppressor"""""""" genes that may be integrally involved in leukemogenesis.
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