The overall objective of this research proposal is the identification of genetic marker relevant for the pathogenesis, diagnosis and clinical monitoring of lymphoid malignancies, including acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). The general experimental plan involves: 1) test the utility of known oncogene alterations as clinico-pathologic markers; 2) identify novel oncogene alterations which are consistently associated with lymphoid malignancies; and 3) develop sensitive and specific assays to monitor disease spread and remission. In particular, the following specific aims will be pursued: 1) Test the utility of oncogene alterations as clinico-pathologic markers. We have already determined that ras oncogene mutations are frequently associated with ALL and MM. We will test the clinico-prognostic relevance of ras oncogene mutations in these two malignancies by screening for ras mutations large panels of ALL and MM cases and correlating the results with a number of relevant clinical parameters. 2) Identification of novel oncogene alterations. Preliminary data indicate that a significant fraction of NHL cases contains DNA sequences which are able to cause the tumorigenic conversion of NIH3T3 cells. These sequences do not correspond to any of the known ras oncogenes. Transforming sequences have been cloned from one case and do not appear to correspond to any known oncogene. We plan to characterize these sequences, identify the putative proto-oncogenes, identify the nature of the activating mutations and determine their frequency in lymphoid malignancies. Eventually, we will test the utility of these alterations as clinico-pathologic markers as in 1). 3) Development and clinico-prognostic testing of assays to monitor disease spread and remission. We have recently developed a polymerase chain reaction (PCR)-based assay which allows the detection of clonal lymphoid cells in virtually all types of B-cell malignancies at a sensitivity of 1/10-5 cells, independent of previous cytogenetic analysis and presence of known chromosomal translocations. We will use this assay to determine: i) the extent of disease spread, i.e. bone marrow, peripheral blood and/or lymphnodes, depending upon the type of malignancy; and ii) the presence of minimal residual disease during remission. The data collected from representative panels of cases will be correlated with relevant clinico- prognostic parameters.
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