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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC004024-09
Application #
2456831
Study Section
Metabolism Study Section (MET)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
1996
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Iqbal, J; Greiner, T C; Patel, K et al. (2007) Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma. Leukemia 21:2332-43
Lenz, Georg; Nagel, Inga; Siebert, Reiner et al. (2007) Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. J Exp Med 204:633-43
Annunziata, Christina M; Davis, R Eric; Demchenko, Yulia et al. (2007) Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12:115-30
Davies, Andrew J; Rosenwald, Andreas; Wright, George et al. (2007) Transformation of follicular lymphoma to diffuse large B-cell lymphoma proceeds by distinct oncogenic mechanisms. Br J Haematol 136:286-93
Kuo, Tracy C; Shaffer, Arthur L; Haddad Jr, Joseph et al. (2007) Repression of BCL-6 is required for the formation of human memory B cells in vitro. J Exp Med 204:819-30
Davis, R Eric; Zhang, Ya-Qin; Southall, Noel et al. (2007) A cell-based assay for IkappaBalpha stabilization using a two-color dual luciferase-based sensor. Assay Drug Dev Technol 5:85-103
Wiestner, Adrian; Tehrani, Mahsa; Chiorazzi, Michael et al. (2007) Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood 109:4599-606
Salaverria, Itziar; Zettl, Andreas; Bea, Silvia et al. (2007) Specific secondary genetic alterations in mantle cell lymphoma provide prognostic information independent of the gene expression-based proliferation signature. J Clin Oncol 25:1216-22
Iqbal, Javeed; Neppalli, Vishala T; Wright, George et al. (2006) BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. J Clin Oncol 24:961-8
Ngo, Vu N; Davis, R Eric; Lamy, Laurence et al. (2006) A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441:106-10

Showing the most recent 10 out of 25 publications