Acute myelogenous leukemia (AML) cells represent a state of impaired differentiation, enhanced growth and survival of the myeloid progenitors. The tight correlation between cytogenetic alterations and response to therapy is indicative of a cause and effect relationship between the genotype and the disease phenotype. Acquired partial or complete deletion of the long arm of chromosome 7 (7q- or -7) seen in 22% of AML cases, constitutes the most common Cytogenetic anomaly and is associated with poor prognosis. The limits of the interstitial 7q deletions may vary from patient to patient, however there are critical regions of overlap that are consistently deleted. We hypothesize an important role for conversion to hemizygosity at these loci in the evolution of the abnormal phenotype. The studies described here are aimed at understanding the biology and clinical course of the disease in patients with poor prognosis. Our investigations will aim at: l) Molecular delineation of the critical regions of loss in chromosome 7 by loss of heterozygosity analyses; 2) Isolation of genomic clones for the critical loci from a normal human genomic library in Yeast Artificial Chromosome vector; 3) Long range restriction map of the clones isolated in #2 and search for rearrangements of the critical loci in poor prognosis patients; 4) a) Determination of the stage of myeloid maturation at which the anomalies of chromosomes 5 and 7 occur; and b) Comparison of growth factor and chemotherapy response in vitro and in vivo of patients with poor prognosis. A correlation will be made between the genotype of chromosomes 5 and 7 loci and the response to therapy. These studies will provide clues on the molecular mechanisms underlying the refractoriness seen in patients with abnormalities of chromosome 5 and 7.

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University of Texas MD Anderson Cancer Center
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