Assistant Professor of Microbiology & Immunology
Ph.D., University of Cologne

Germinal center B-Cell differentiation: physiology and disruption in malignancy

The hallmark of antibody-dependent immune responses is the generation of high-affinity antibodies in the germinal center (GC)-reaction by immunoglobulin variable region gene somatic hypermutation. The GC-reaction is also the main source of plasma cells that help to eliminate the infection, and of memory B cells that establish life-long immunity to the pathogen through their ability to mount an effective antigen-recall response. However, the beneficial role of GC B cells in immunity is somewhat counterbalanced by their detrimental role in lymphomagenesis, as it was found that the majority of B-cell lymphomas originate from GC B cells or cells that have passed through the GC-reaction.

The laboratory's research interests are focused on the elucidation of the molecular mechanisms that govern the differentiation of GC B cells into memory or plasma cells, and on the investigation as to how those mechanisms are disrupted in B-cell malignancies. Since genomic lesions in B cells can lead to the deregulated expression of developmentally important transcription factors - thereby disturbing the control of cellular processes such as proliferation, apoptosis or differentiation - these studies are expected to provide insights into the oncogenic transformation of mature B-cell lymphomas and leukemias.

Elucidating the mechanisms controlling the 'exit' of the germinal center reaction and the decision to become a memory or a plasma cell. A major question in immunology is how a mature B cell differentiates into a memory B cell or a plasma cell during the antibody-dependent immune response. Advances in technology have recently allowed a more precise dissection of the phenotypes of GC and post-GC B cells and the transcriptional programs that are responsible for those phenotypes. Transcription factors that are specifically expressed in GC B cell subpopulations will be studied for their potential role as molecular switches in memory versus plasma cell differentiation. Results from those analyses will also help to better define the phenotypes of the heterogeneous GC-derived B-cell lymphomas (non-Hodgkin and Hodgkin lymphomas) and are expected to provide insights into their pathogenesis.

Understanding the physiology of antigen-experienced (post-germinal center) B cells and its dysregulation in B-cell tumors. This topic has gained particular attention in light of the realization that a subgroup of B-cell malignancies, most notably B-cell chronic lymphocytic leukemia (CLL), seem to originate from the oncogenic transformation of an antigen-experienced memory or marginal zone B cell instead of a GC B cell, which represents the presumed precursor of most lymphoma subtypes. The goal is to determine how the specific genetic alterations, epigenetic changes as well as susceptibility loci found in this subgroup of tumors affect the physiology of the antigen-experienced B cell, and whether this knowledge can be exploited for improved therapies aimed at those tumors.

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1. De Silva, N.S., Simonetti, G., Heise, N. and Klein, U. (2012) The diverse roles of IRF4 in late germinal center B-cell differentiation. Immunol. Rev. 247: 73-92.
2. Lia, M., Carette, A., Tang, H., Shen, Q., Mo, T., Bhagat, G., Dalla-Favera, R. and Klein, U. (2011) Functional dissection of the chromosome 13q14 tumor suppressor locus using transgenic mouse lines. Blood 119: 2981-2990. (Plenary Paper; comment in Blood 2012 119: 2974-2975)
3. Klein, U. and Ghosh, S. (2011) The two faces of NF-kB signaling in cancer development and therapy. Cancer Cell 20: 556-558.
4. Klein, U. and Pasqualucci, L. (2010) B-cell receptor signaling derailed in lymphomas. Immunology and Cell Biology 88: 346-347.
5. Klein, U., Lia, M., Crespo, M., Siegel, R., Shen, Q., Mo, T., Ambesi-Impiombato, A., Califano, A., Migliazza, A., Bhagat, G. and Dalla-Favera, R. (2010) The DLEU2/miR-15a/16-1 cluster controls B-cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 17: 28-40.
6. Wang, K., Saito, M., Bisikirska, B.C., Alvarez, M.J., Lim, W.K., Rajbhandari, P., Shen, Q., Nemenman, I., Basso, K., Margolin, A.A., Klein, U., Dalla-Favera, R. and Califano, A. (2009) Genome-wide identification of post-translational modulators of transcription factor activity in human B cells. Nat. Biotechnol. 27: 829-839.
7. Zheng, Y., Chaudhry, A., Kas, A., deRoos, P., Kim, J.M., Chu, T.-T., Corcoran, L., Treuting, P., Klein, U. and Rudensky, A.Y. (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control Th2 responses. Nature 458: 351-356.
8. Schenten, D., Kracker, S., Esposito, G., Franco, S., Klein, U., Murphy, M., Alt, F.W. and Rajewsky, K. (2009) Ablation of Polζ in B-cells impairs germinal center reaction, class switching and genome stability. J. Exp. Med. 206: 477-490.
9. Klein, U. and Dalla-Favera, R. (2008) Germinal centres: role in B-cell physiology and malignancy. Nat. Rev. Immunol. 8: 22-33.
10. Klein, U. Gene expression profiling in the study of CLL. (2008) Chapter 2. Chronic Lymphocytic Leukemia. Editors: S. O'Brien & J.G. Gribben, Informa Healthcare, USA: 19-33.
11. Klein, U. and Dalla-Favera, R. (2007) Unexpected steps in plasma-cell differentiation. Immunity 26: 543-544. Review.
12. Klein, U., Casola, S., Cattoretti, G., Shen, Q., Lia, M., Mo, T. , Ludwig, T., Rajewsky, K. and Dalla-Favera, R. (2006) Transcription factor IRF4 controls plasma cell differentiation and class switch recombination. Nat. Immunol. 7: 773-782.
13. Basso, K., Margolin, A., Stolovitzky, G.A., Klein, U., Dalla-Favera, R. and Califano, A. (2005) Reverse engineering of regulatory networks in human B cells. Nature Genetics 37: 382-390.
14. Klein, U., Gloghini, A., Gaidano, G., Chadburn, A., Cesarman, E., Dalla-Favera, R. and Carbone, A. (2003) Gene expression profile analysis of AIDS-related primary effusion lymphoma (PEL) suggests a plasmablastic derivation and identifies PEL-specific transcripts. Blood 101: 4115-4121.
15. Klein, U., Tu, Y., Stolovitzky, G.A., Keller, J.L., Haddad, J., Miljkovic, V., Cattoretti, G., Califano, A. and Dalla-Favera, R. (2003) Transcriptional analysis of the germinal center reaction. Proc. Natl. Acad. Sci. U.S.A. 100: 2629-2644.
16. Klein, U., Tu, Y., Stolovitzky, G.A., Mattioli, M., Cattoretti, G., Husson, H., Freedman, A., Inghirami, G., Cro, L., Baldini, L., Neri, A., Califano, A. and Dalla-Favera, R. (2001) Gene expression profiling of B-cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B-cells. J. Exp. Med. 194: 1625-1638.
17. Kuppers, R., Klein, U., Hansmann, M.-L. and Rajewsky, K. (1999) Cellular origin of human B-cell lymphomas. N. Engl. J. Med. 341: 1520-1529.
18. Klein, U., Rajewsky, K. and Kuppers, R. (1998) Human Immunoglobulin (Ig)M+IgD+ peripheral blood B-cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B-cells. J. Exp. Med. 188: 1679-1689.
19. Klein, U., Kuppers, R. and Rajewsky, K. (1997) Evidence for a large compartment of IgM-expressing memory B-cells in humans. Blood 89: 1288-1298.