Department of Microbiology & Immunology

Columbia University in the City of New York
Ulf Klein, Ph.D.
Assistant Professor of Microbiology & Immunology
Ph.D., University of Cologne

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

Research
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 generates plasma cells and memory B cells that help to eliminate the infection and establish life-long immunity to the pathogen. However, the beneficial role of GC B cells in immunity is somewhat counterbalanced by their detrimental role in lymphomagenesis, since most B-cell lymphomas originate from B 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, and determining how those mechanisms are disrupted in B-cell lymphomas and leukemias. 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-cells.

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 B cell differentiates into a memory B cell or a plasma cell during the T cell-dependent immune response. 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 may help to better define the phenotypes of the heterogeneous GC-derived B-cell lymphomas.

Understanding the physiology of quiescent, antigen-experienced B cells. A subgroup of B-cell malignancies that include B-cell chronic lymphocytic leukemia (CLL) originate from the oncogenic transformation of quiescent, antigen-experienced B cells rather than from proliferating GC B cells. The goal is to determine how the specific genetic alterations, epigenetic changes and susceptibility loci found in this subgroup of tumors affect the physiology of the antigen-experienced B cell. This knowledge may be exploited for improved therapies aimed at those tumors.

Selected Publications

  1. Heise, N., De Silva, N.S., Silva, K., Carette, A., Simonetti, G., Pasparakis, M. and Klein, U. (2014). Germinal center B-cell maintenance and differentiation are controlled by distinct NF-kappaB transcription factor subunits. J. Exp. Med. 211: 2103-2118.
  2. Simonetti, G., Bertilaccio, M.T.S., Ghia, P. and Klein, U. (2014) Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy. Blood 124: 1010-1019.
  3. Klein, U. (2014) Programming plasma cell survival. J. Exp. Med. 211: 744. (Insights Article)
  4. Simonetti, G., Carette, A., Silva, K., Wang, H., De Silva, N., Heise, N., Siebel, C.W., Shlomchik, M.J. and Klein, U. (2013) IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity. J. Exp. Med. 210: 2887-2902.
  5. Ochiai, K., Maienschein-Cline, M., Simonetti, G., Chen, J., Rosenthal, R., Brink, R., Chong, A.S., Klein, U., Dinner, A.R., Singh, H. and Sciammas, R. (2013) Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity 38: 918-929.
  6. Nayar, R., Enos, M., Prince, A., Shin, H., Hemmers, S., Jiang, J.-K., Klein, U., Thomas, C.J. and Berg, L.J. (2012) TCR signaling via ITK and IRF4 regulates CD8+ T cell differentiation. Proc. Natl. Acad. Sci. USA. 109: E2784-E2793.
  7. 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.
  8. 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)
  9. Eguchi, J., Wang, X., Yu, S., Kershaw, E.E., Chiu, P.C., Dushay, J., Estall, J.L., Klein, U., Maratos-Flier, E. and Rosen, E.D. (2011) Transcriptional control of adipose lipid handling by IRF4. Cell Metabolism 13: 249-259.
  10. Klein, U. and Ghosh, S. (2011) The two faces of NF-kB signaling in cancer development and therapy. Cancer Cell 20: 556-558.
  11. 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.
  12. 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.
  13. 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.
  14. Klein, U. and Dalla-Favera, R. (2008) Germinal centres: role in B-cell physiology and malignancy. Nat. Rev. Immunol. 8: 22-33.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.

Assistant Professor Ulf Klein
Phone: 212-851-5243
Lab Phone: 212-851-5251
Fax: 212-851-4660
Email:  uk30@columbia.edu


Department of Microbiology & Immunology, Columbia University + 701 W. 168 St., HHSC 1208 New York, NY 10032 Tel. 212-305-3647