This application addresses the etiology and pathogenesis of acute lymphoblastic leukemias (ALL), with particular emphasis on the molecular biology of chromosomal abnormalities implicated in their causation. The long-term objectives are to study the genes and-their products which are involved in the pathogenesis of these leukemias with the aim of establishing more meaningful diagnostic and prognostic subclassifications based on molecular abnormalities.
The aims of this proposal are to isolate and characterize the cellular oncogenes implicated in a specific subset of lymphoid and myeloid leukemias that carry translocations involving chromosomes llq23 and 19pl3. The experimental approach will consist of constructing a physical map of the short arm of chromosome 19 (19p) showing the relative locations of 19p translocation breakpoints present in various leukemia cell lines. Over fifty probes or genes known to map to 19p or llq23 will be used on chromosome in situ hybridizations to determine their regional localization with respect to various t(11;19) translocations. Probes flanking t(11;19) translocation breakpoints in T-lineage ALL and common ALL cell lines will be tested for their proximity to these translocations using pulsed-field gel electrophoresis. Those that detect DNA rearrangements associated with t(11;19) translocations will be used to molecularly clone breakpoint DNA and to isolate and characterize llq23 and 19pl3 genes involved by these translocations. The molecular reagents resulting from these studies will be employed in long-term efforts to dissect the contributions of llq23 /or 19pl3 genes to leukemia pathogenesis by means of various gene transfer experiments to establish in vitro and animal models of t(11;19)-carrying leukemias. These reagents will also be used to study patients with leukemia to establish the prevalence of llq23 and 19pl3 oncogene involvement and its prognostic and diagnostic significance.
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