PATHOGENESIS OF HUMAN T-CELL LEUKEMIAS/LYMPHOMAS

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The goal of this proposal is to identify and characterize possible genes involved in the pathogenesis of T-cell leukemias and lymphomas with the inversion/translocation of the region q11.2-q32.2 of chromosome 14 in man. cDNA probes specific for the alpha-chain locus of the T-cell receptor ion 14q11.2) will be used in Southern blot hybridization to clone the breakpoint involved in the 14q11.1-q32.2 translocation/inversion. The proto-oncogene on band q32.2 of chromosome 14, for which we propose the name of tcl-1 (T-cell leukemia/lymphoma-1) will be identified by "walking" upstream to the alpha-chain locus, as in analogous work done with B-cell malignancies carrying translocations involving the immunoglobulin heavy chain locus. In doing so, we will obtain nucleic acid probes to identify and characterize the tcl-1 gene, a proto-oncogene which appears to be unrelated to any of the known retrovirus oncogenes described to date. The tcl-1 gene will be entirely sequenced; the genetic elements capable of activating the proto-oncogene will be defined. We will study the regulation of its expression in normal versus malignant T-cells, in quiescent versus proliferating T-cells and in a variety of normal and neoplastic tissues. We will also produce antibodies against the tcl-1 gene product to determine its cellular location and to be used for its characterization and purification. This study should result in a better understanding of the genetic mechanisms leading to T-cell neoplasia and should provide probes to be used in the diagnosis of this human malignancy.