Our investigations of the myc gene in small non-cleaved cell lymphomas have led us into a more basic study of myc structure/function relationships. We have 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 in and around the phosphorylatable moieties threonine 58 and serine 62. These mutations appear to be selected during tumorigenesis, and the mutant myc proteins have increased growth associated activities as compared to the normal myc protein. In collaboration with Dr. Chi V. Dang of Johns Hopkins University, we have found that these myc mutant proteins have lost the ability to be regulated by the Rb-like protein p107. We have found that the reason for this is that p107 mediates the phosphorylation of myc at threonine 58 and serine 62 through the formation of cyclin A/CDK/p107 complexes. We previously reported that the bcl-1 major breakpoint region is associated with mantle cell lymphoma. We now show that lymphomatous polyposis coli, a lymphocytic lymphoma confined to the intestinal tract, is also characterized by bcl-1 rearrangements, and is part of the spectrum of mantle cell lymphoma. We have completed several studies regarding the role of the cyclin dependent kinase inhibitors in lymphomagenesis. These include p15, p16, and p18. We have 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 also completed several projects in the past year exploring the role of several newly described genes in lymphomas. These include the LAZ3 (BCL-6) gene (see major findings) and the anaplastic lymphoma associated gene nucleophosmin. We have initiated new studies into the role of the HHV-8 in lymphomas arising in AIDS.
