Department of Microbiology & Immunology

Columbia University in the City of New York
Riccardo Dalla-Favera, M.D.
Professor of Microbiology & Immunology, Pathology & Cell Biology, Genetics & Development, Percy & Joanne Uris Professor of Clinical Medicine and Director, Institute for Cancer Genetics
M.D., University of Milan

Identification of the genetic lesions involved in the pathogenesis of human B cell tumors

Research
The general goal of this laboratory is to elucidate the pathogenesis of cancers derived from B lymphocytes, known as B cell lymphomas. These tumors originate from the malignant transformation of germinal center B cells, via acquisition of genomic lesions involving oncogenes and tumor suppressor genes. We wish to identify these lesions, determine the mechanism by which they occur and elucidate the contribution of each lesion to tumor development using genetically modified mouse models. These studies are also aimed at identifying targets for therapeutic intervention. Specific lines of investigation include:

1) Integrate genome-wide genomic and transcriptomic analyses to identify the genetic lesions involved in the development of Diffuse Large B Cell Lymphoma (DLBCL) and Chronic Lymphocytic Leukemia (CLL), the two most common forms of B cell malignancies.

2) Elucidate the physiologic role of the genes altered in DLBCL and CLL by identifying their function in germinal center development through the combination of biochemical and functional assays as well as genetically engineered mice with specific gene deletion in germinal center B cells.

3) Identify the pathologic role of DLBCL- and CLL-associated genetic lesions by recapitulating them in the germinal center of mice.

4) Test novel therapeutic approaches for their ability to target newly discovered genetic lesions and cellular pathways altered in tumors.

Selected Publications

  1. Dominguez-Sola, D., Kung, J., Holmes, A.B., Wells, V.A., Mo, T., Basso, K. and Dalla-Favera, R. (2015) The FOXO1 transcription factor instructs the germinal center dark zone program. Immunity 43: 1064-1074.
  2. Zhang, J., Dominguez-Sola, D., Hussein, S., Lee, J.E., Holmes, A.B., Bansal, M., Vlasevska, S., Mo, T., Tang, H., Basso, K., Ge, K., Dalla-Favera, R. and Pasqualucci, L. (2015) Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nature Med. 21: 1190-1198.
  3. Weinstock, D.M., Dalla-Favera, R., Gascoyne, R.D., Leonard, J.P., Levy, R., Lossos, I.S., Melnick, A.M., Nowakowski, G.S., Press, O.W., Savage, K.J., Shipp, M.A. and Staudt, L.M. (2015) A roadmap for discovery and translation in lymphoma. Blood 125: 2175-2177.
  4. Basso, K. and Dalla-Favera, R. (2015) Germinal centres and B cell lymphomagenesis. Nat Rev Immunol. 15: 172-184.
  5. Trimarchi, T., Bilal, E., Ntziachristos, P., Fabbri, G., Dalla-Favera, R., Tsirigos, A. and Aifantis, I. (2014) Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell 158: 593-606.
  6. Schneider, C., Setty, M., Holmes, A.B., Maute, R.L., Leslie, C.S., Mussolin, L., Rosolen, A., Dalla-Favera, R. and Basso, K. (2014) MicroRNA 28 controls cell proliferation and is down-regulated in B-cell lymphomas. Proc. Natl. Acad. Sci. U.S.A. 111: 8185-8190.
  7. Pasqualucci, L., Khiabanian, H., Fangazio, M., Vasishtha, M., Messina, M., Holmes, A.B., Ouillette, P., Trifonov, V., Rossi, D., Tabbo, F., Ponzoni, M., Chadburn, A., Murty, V.V., Bhagat, G., Gaidano, G., Inghirami, G., Malek, S.N., Rabadan, R. and Dalla-Favera, R. (2014) Genetics of follicular lymphoma transformation. Cell Rep. 6: 130-140.
  8. Fabbri, G., Khiabanian, H., Holmes, A.B., Wang, J., Messina, M., Mullighan, C.G., Pasqualucci, L., Rabadan, R. and Dalla-Favera, R. (2013) Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J. Exp. Med. 210: 2273-2288.
  9. Ying, C.Y., Dominguez-Sola, D., Fabi, M., Lorenz, I.C., Hussein, S., Bansal, M., Califano, A., Pasqualucci, L., Basso, K. and Dalla-Favera, R. (2013) MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nature Immunol. 14: 1084-1092.
  10. Basso, K., Schneider, C., Shen, Q., Holmes, A.B., Setty, M., Leslie, C. and Dalla-Favera, R. (2012) BCL6 positively regulates AID and germinal center gene expression via repression of miR-155. J. Exp. Med. 209: 2455-2465.
  11. Dominguez-Sola, D., Victora, G.D., Ying, C.Y., Phan, R.T., Saito, M., Nussenzweig, M.C. and Dalla-Favera, R. (2012) The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nature Immunol. 13: 1083-1091.
  12. Challa-Malladi, M., Lieu, Y.K., Califano, O., Holmes, A., Bhagat, G., Dominguez-Sola, D., Murty, V.V., Pasqualucci, L. and Dalla-Favera, R. (2011) Combined genetic inactivation of beta2-microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B-cell lymphoma. Cancer Cell 13: 728-740.
  13. Pasqualucci, L. Trifonov, V., Fabbri, G., Ma, J., Rossi, D., Chiarenza, A., Wells, V.A., Grunn, A., Messina, M., Elliot, O., Chan, J., Bhagat, G., Chadburn, A., Gaidano, G., Mullighan, C. G., Rabadan, R. and Dalla-Favera, R. (2011) Analysis of the coding genome of diffuse large B-cell lymphoma. Nature Genetics 43: 830-837.
  14. Fabbri, G., Rasi, S., Rossi, D., Trifonov, V., Khiabanian, H., Ma, J., Grunn, A., Fangazio, M., Capello, D., Monti, S., Cresta, S., Gargiulo, E., Forconi, F., Guarini, A., Arcaini, L., Paulli, M., Laurenti, L., Larocca, L.M., Marasca, R., Gattei, V., Oscier, D., Bertoni, F., Mullighan, C.G., Foa, R., Pasqualucci, L., Rabadan, R., Dalla-Favera, R. and Gaidano, G. (2011) Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J. Exp. Med. 208: 1389-1401.
  15. Pasqualucci, L., Dominguez-Sola, D., Chiarenza, A., Fabbri, G., Grunn, A., Trifonov, V., Kasper, L.H., Lerach, S., Tang, H., Ma, J., Rossi, D., Chadburn, A., Murty, V.V., Mullighan, C.G., Gaidano, G., Rabadan, R., Brindle, P.K. and Dalla-Favera, R. (2011) Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471: 189-195.
  16. Mandelbaum, J., Bhagat, G., Tang, H., Mo, T., Brahmachary, M., Shen, Q., Chadburn, A., Rajewsky, K., Tarakhovsky, A., Pasqualucci, L. and Dalla-Favera, R. (2010) BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell 18: 568-579.
  17. 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.
  18. Compagno, M., Lim, W.K., Grunn, A., Nandula, S.V., Brahmachary, M., Shen, Q., Bertoni, F., Ponzoni, M., Scandurra, M., Califano, A., Bhagat, G., Chadburn, A., Dalla-Favera, R. and Pasqualucci, L. (2009) Mutations of multiple genes cause deregulation of the NF-kB pathway in diffuse large B-cell lymphoma. Nature 459: 717-721.
  19. Basso, K., Sumazin, P., Morozov, P., Schneider, C., Maute, R.L., Kitagawa, Y., Mandelbaum, J., Haddad, J. Jr., Chen, C.Z., Califano, A. and Dalla-Favera, R. (2009) Identification of the human mature B cell miRNome. Immunity 30: 744-752.
  20. Pasqualucci, L., Bhagat, G., Jankovic, M., Compagno, M., Smith, P., Muramatsu, M., Honjo, T., Morse, H.C. 3rd, Nussenzweig, M.C. and Dalla-Favera, R. (2008) AID is required for germinal center-derived lymphomagenesis. Nature Genet. 40: 108-112.
  21. Phan, R.T., Saito, M., Kitagawa, Y., Means, A.R. and Dalla-Favera, R. (2007) Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells. Nature Immunol. 8: 1132-1139.
  22. Saito, M., Gao, J., Basso, K., Kitagawa,Y., Smith, PM., Pasqualucci, L., Dalla-Favera, R: (2007) A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell 12: 280-292.
  23. Dominguez-Sola, D., Ying, C.Y., Grandori, C., Ruggiero, L., Chen, B., Galloway, D.A., Gu, W., Gautier, J. and Dalla-Favera, R. (2007) Non-transcriptional control of DNA replication by c-myc. Nature 448: 445-451.

Professor Riccardo Dalla-Favera
Director, Institute for Cancer Genetics
Phone: 212-851-5273
Fax: 212-851-5256
Email:  rd10@columbia.edu


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