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Inducible human myeloid leukemic cell lines provide experimental access to events in both leukemic cell differentiation and normal hematopoiesis. It is possible that cytodifferentiation strategies could ultimately provide alternatives to ones based upon cytodestruction for the clinical management of human hematopoietic malignancies. Anti-sense RNA transfection analysis offers a means for directly assessing the functional role of certain genes, e.g., protooncogenes and colony stimulating factor (CSF) genes, in leukemic differentiation programs. Recent studies in our laboratory have established the utility of high copy number episomal replicons for the effective anti-sense RNA- mediated inhibition of gene expression in human hematopoietic cells. The proposed experiments are directed at: 1) optimization of episomal replicon-based constitutive and inducible transgene expression in human hematopoietic cells, 2) investigation of protooncogene and CSF mRNA expression in a panel of inducible human myeloid leukemic cell lines (HL-60, ML-1, K562, KG-1, U937), with specific attention to the chronology and lineage specificity of changes in gene expression, 3) anti-sense RNA mutational analysis to determine which, if any, expressed protooncogenes and CSFs play an obligatory role in leukemic differentiation, and 4) derivation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) induction-specific HL-60 cDNAs through differential screening and cloning methodologies and functional evaluation of these genes through anti-sense RNA transfection experiments. The proposed studies should contribute to an understanding of the molecular mechanisms underlying normal and leukemic hematopoiesis, and could provide general insights into the effective use of anti-sense RNA technology in studying the role of specific genes in human hematopoietic cell function and differentiation.
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