Studies of tumor-specific chromosome abnormalities have provided important insights into the genetic events that underlie oncogenesis. The most prevalent chromosome defect in the spectrum of adult T cell tumors is an inversion of chromosome 14.
The aim of this project is to determine how the inv(14)(q11;q32) chromosome inversion and the related t(14;14)(q11;q32) translocation contribute to the development of human T cell tumors. Preliminary data provide strong evidence for the existence of a cellular proto-oncogene located somewhere downstream of the immuno-globulin heavy chain gene on chromosome band 14q32. Activation of the putative 14q32 oncogene by transposition into the T cell receptor alpha chain gene on 14q11 may be the mechanism by which inv(14) and t(14;14) participate in T cell oncogenesis. To investigate this possibility, we must initially define the structure and pattern of expression of the 14q32 oncogene during normal T cell development, and subsequently examine the manner in which its expression is perturbed upon transposition into the T cell receptor alpha chain gene. Initially, genomic DNA that encompasses the 14q32 breakpoints of inv(14)/t(14;14) chromosomes will be isolated by the use of pulsed- field gel electrophoresis and molecular cloning methodology. Genomic 14q32 DNA probes will then be used to identify 14q32 RNA transcripts in T lymphocytes, and to establish the pattern of 14q32 transcription during thymic development. Transcription of 14q32 sequences from normal and inverted chromosomes 14 will be compared so as to determine the impact of chromosome rearrangement on expression of the 14q32 oncogene. The amino acid coding potential of 14q32 transcripts will be examined by cDNA sequencing, and this information will be used to produce monoclonal antibodies specific for the 14q32 oncogene. Finally, the malignant properties of the 14q32 oncogene will be investigated in tranfection of cultured NIH-3T3 cells and controlled expression in transgenic mice.
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