We found that Burkitt's and AIDS-associated lymphomas with 8q24 translocations have a very high frequency of clustered mutations in the transcriptional activation domain of myc centered around threonine 58 and serine 62. These mutations appear to be selected during tumorigenesis, and the mutant myc proteins have increased growth associated activities compared to normal myc. In collaboration with Dr. Chi V. Dang, we found that these mutant proteins have lost the ability to be downregulated by the Rb-like protein p107. Our studies uncovered a mechanism through which p107 mediates phosphorylation of wild type myc at threonine 58 and serine 62 through the formation of a cyclin A/CDK/p107 complex. The mutant tumor derived proteins are incapable of becoming phosphorylated. We have continued to study several other Myc mutant proteins and have preliminarily identified a different set of mutant proteins in which the ability of Myc to induce apoptosis appears to be deficient. We previously reported that the bcl-1 major breakpoint region is associated with mantle cell lymphoma (MCL). We now show that multiple lymphomatous polyposis, a lymphocytic lymphoma involving the intestinal tract, is also characterized by bcl-1 rearrangements, and is part of the spectrum of MCL. We have completed several studies concerning the role of the CDK inhibitors p15, p16, and p18, in lymphomagenesis. We found deletions of both p15 and 16 in lymphoblastic leukemia/lymphomas, but not in other lymphoid tumors. We have not detected abnormalities of p18 in any of the tumors studied. We have studied the t(2;5) translocation and its molecular counterpart the NPM/ALK fusion gene in a series of lymphomas and found this abnormality to be highly specific for anaplastic lymphomas. We have cloned and sequenced 7 cases, and found that although the breakpoints are not highly clustered, most can be detected using a long distance PCR assay. We have studied the expression of cytotoxic granule constituents, TIA-1 and perforin, in anaplastic lymphomas (ALCL). We have found that most express one or more of these proteins, suggesting that ALCL is related to the cytotoxic T-cell lineage. We have studied the distribution of the new Kaposi's sarcoma-related virus HHV-8 in AIDS and non-AIDS lymphomas and found the virus mainly within a group of body cavity lymphomas that arise in AIDS.
