Dr. Staudt's laboratory is currently focused on understanding the molecular pathogenesis of human leukemias and lymphomas caused by nuclear oncogenes. A major area of interest is in diffuse large cell lymphoma (DLCL) caused by the BCL-6 oncogene. DLCL is a malignancy of mature B lymphocytes that accounts for roughly 40% of cases of non-Hodgkin's lymphoma. The BCL-6 gene is translocated in as many as 40% of cases of DLCL and 70-80% of DLCL cases have mutations in a presumptive 5' regulatory region of the gene. BCL-6 is also frequently rearranged in AIDS-associated diffuse large cell lymphomas. The coding region of BCL-6 remains unmutated in the lymphomas suggesting that dysregulation of the gene underlies the lymphomagenesis. BCL-6 encodes a zinc finger protein which has a novel homology domain at its amino terminus, the POZ domain, which is shared by a subset of zinc finger factors. The laboratory has shown that the BCL-6 protein can function as a potent transcriptional repressor when bound to its cognate DNA binding sites and that much of this repressive activity is mediated by the POZ domain. Although BCL-6 mRNA expression is widespread, BCL-6 protein expression is largely restricted to germinal center B cells by a post-transcriptional mechanism. To gain insight into the normal biological function of BCL-6, the gene was mutated in the mouse germ line using homologous recombination in embryonic stem cells. Mice homozygous for the mutant BCL-6 allele are born normally but display growth retardation shortly after birth and frequently die within 1 to 4 weeks. The knockout mice characteristically develop a severe inflammatory myocarditis and a pulmonary vasculitis. Upon immunization with a conventional T cell-dependent antigen, the BCL-6 knockout mice fail to generate germinal centers and do not mount an IgG immune response. Strikingly, the spleens of the immunized knockout mice become infiltrated with large numbers of granulocytes. These data show that BCL-6 is required to initiate a normal germinal center immune response and further is required to prevent undesired inflammatory responses in the myocardium and lung and in the spleen following immunization. These findings lead to the working model that BCL-6 dysregulation causes diffuse large cell lymphoma by promoting B cell proliferation in a pseudo-germinal center reaction.
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