The goal of our research continues to be the investigation of the role played by chromosome changes in the etiology and clinical behavior of human leukemia and lymphoma utilizing our unique tumor tissue and clinical resources. During the past six years of this grant we have made significant progress and new observations in identifying new clinical, histopathological, cytogenetic, and molecular subsets, especially of lymphoma. The emphasis of this application is to address a number of specific mechanistically oriented questions deriving from our observations of nonrandom chromosome changes and their relationship to leukemia and lymphoma development and progression. These are: (1) Mechanisms of chromosome instability and gene deregulation in lymphoma: We will obtain new insights into the molecular basis of chromosome breakage by sequencing cloned translocation junctions, notably those involving the immunoglobulin genes with c-myc, bcl-1, and ncl-2. We will investigate c-myc deregulation brought about by mutational changes in the exon 1/intron 1 region and its role in the development of histologically and clinically distinct subsets of lymphoma (follicular, diffuse large cell) carrying the t(8;14) translocation. For these studies we will directly sequence the target region following in vitro amplification by the polymerase chain reaction (PCR) technique. (2) Genetic mechanism of lymphoma progression: We will investigate the role played by gene amplification in the progression to very high grade of certain subsets of lymphoma. For this we will clone amplified regions from lymphomas with HSRs and DMs using the in-gel renaturation technique. (3) Genetic basis of leukemia onset or relapse in response to specific treatment: We will investigate our hypothesis that activating ras gene mutations represent a common mechanism for the de novo leukemogenesis that occurs in patients who have been treated for and cured of a prior neoplasm and relapse and de novo leukemogenesis that occurs in patients treated for leukemia by bone marrow transplantation. The methodology for detection of these mutations will be the PCR technique. Finally, we will continue our productive studies of histologic correlation and prognostic significance of chromosome changes in lymphoma. In these the detection of clonal chromosome abnormalities will be enhanced by the use of molecular probes.
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