Researcher’s Profile

Riccardo Dalla-Favera, MD

Director, Institute for Cancer Genetics
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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.

Email: rd10@cumc.columbia.edu

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Molecular genetics of cancer; molecular pathogenesis of lymphoma and leukemia; genetic control in lymphoid tissue development.

Research Statement: 

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. 

Publications: 

   Dominguez-Sola, D., Ying, C.Y., Grandori, C., Ruggiero, L., Chen, B., Galloway, D.A., Gu, W., Gautier, J., Dalla-Favera. R.  Non-transcriptional control of DNA replication by c-myc.  Nature. 448(7152):445-51, 2007.

   Saito, M., Gao, J., Basso, K., Kitagawa , Y., Smith, PM., Pasqualucci, L., Dalla-Favera, R. 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(3):280-92, 2007.

   Phan, RT., Saito, M., Kitagawa, Y., Means, A., Dalla-Favera, R.  Genotoxic stress regulates expression of the BCL6 proto-oncogene in germinal-center B cells.  Nat Immunol. 8(10):1132-1139, 2007.

   Pasqualucci, L., Bhagat, G., Jankovic, M., Compagno, M., Smith, P., Morse III, HC. Nussenzweig, MC., Dalla-Favera, R.  AID is required for germinal center derived lymphomagenesis. Nat Genet. 40(1):108-12, 2008.

   Basso, K., Sumazin, P., Morozov, P., Schneider, C., Maute, R.L., Kitagawa, Y., Mandelbaum,  J., Haddad, J. Jr., Chen, C.Z., Califano, A., Dalla-Favera, R. Identification of the human mature B cell miRNome. Immunity. 30(5):744-52, 2009

  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.  Mutations of multiple genes cause deregulation of the NF-kB pathway in diffuse large B-cell lymphoma. Nature. 459:717-21, 2009

Klein, U., Lia, M., Crespo, M., Siegel, R., Shen, Q., Mo, T., Ambesi-Impiombato, A., Califano, A., Migliazza, A., Bhagat, G., Dalla-Favera, R. The DLEU2/miR-15a/16-1 cluster controls B-cell proliferation and its deletion leads to chronic lymphocytic leukemia.  Cancer Cell. 17(1):28-40, 2010

Basso, K., Saito, M. Sumazin, P., Margolin, A.A., Wang, K., Lim, W. K., Kitagawa, Y., Schneider, C., Alvarez, M.J., Califano, A., Dalla-Favera, R. Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal-center B cells. Blood. 115(5):975-984, 2010

Mandelbaum, J., Bhagat, G., Tang, H., Mo, T., Brahmachary, M., Shen, Q.,  Chadburn, A., Rajewsky, K., Tarakhovsky, A., Pasqualucci L., and Dalla-Favera, A. BLIMP1 is a tumor suppressor gene frequently disrupted in activated B-cell like diffuse large B cell lymphoma. Cancer Cell. 18(6):568-79, 2010.

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., V., Murty, V.V., Mullighan, C.G., Gaidano, G., Rabadan, R., Brindle, P.K., Dalla-Favera, R. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 471: (7337)189-95, 2011

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. Analysis of the Coding Genome of Diffuse Large B-Cell Lymphoma. Nat Genet. 43(9):830-7, 2011.

Challa-Malladi, M., Lieu, Y.K., Califano, O., Holmes, A., Bhagat, G., Dominguez-Sola, D., Murty, V.V., Pasqualucci, L., Dalla-Favera, R. Combined Genetic Inactivation of Beta2-Microglobulin and CD58 Reveals Frequent Escape from Immune Recognition in Diffuse Large B-cell Lymphoma. Cancer Cell. 13:20(6):728-40, 2011

Dominguez-Sola, D., Victora, G.D., Ying, C.Y., Phan, R.T., Saito, M., Nussenzweig, M.C., Dalla-Favera, R. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat Immunol. 13(11):1083-91, 2012

Ying, C.Y., Dominguez-Sola, D., Fabi, M., Lorenz, I.C., Hussein, S., Bansal, M., Califano, A., Pasqualucci, L., Basso, K., Dalla-Favera, R. MEF2B mutations lead to deregulated expression of the BCL6 oncogene in diffuse large B cell lymphoma.  Nat Immunol. 10:1084-92, 2013

Pasqualucci, L., Khiabanian, H., Fangazio, M., Vasishtha, M., Messina, M., Holmes, A.B., Ouillette, P., Trifonov, V., Rossi, D., Tabbò, F., Ponzoni, M., Chadburn, A., Murty, V.V., Bhagat, G., Gaidano, G., Inghirami, G., Malek, S.N., Rabadan, R., Dalla-Favera, R. Genetics of Follicular Lymphoma Transformation. Cell Rep. 16;6(1):130-40, 2014

Trimarchi, T., Bilal, E., Ntziachristos, P., Fabbri, G., Dalla-Favera, R., Tsirigos, A., Aifantis, I. Genome-wide Mapping and Characterization of Notch-Regulated Long Noncoding RNAs in Acute Leukemia. Cell. 158(3):593-606, 2014

Basso, K., Dalla-Favera, R. Germinal Centres and B cell lymphomagenesis. Nat Rev Immunol 15(3):172-84, 2015

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., Pasqualucci, L. Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nat Med. 21(10):1190-8, 2015

Dominguez-Sola, D., Kung, J., Holmes, A.B., Wells, V.A., Mo, T., Basso, K., Dalla-Favera, R. The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program. Immunity. 43(6):1064-74, 2015

Fabbri, G., Dalla-Favera, R. The molecular pathogenesis of chronic lymphocytic leukaemia. Nat Rev Cancer, 16(3):145-62, 2016

Zhang, J. Vlasevska, S., Wells, V.A., Nataraj, S., Holmes, A.B., Duval, R., Meyer, S.N., Mo, T., Basso, K., Brindle, P.K., Hussein, S., Dalla-Favera, R., Pasqualucci, L. The Crebb Acetyltransferase is a Haploinsufficient Tumor Suppressor in B Cell Lymphoma. Cancer Discov. 7(3):322-337, 2017

Fabbri, G., Holmes, A.B., Viganotti, M., Scuoppo, C., Belver, L., Herranz, D., Yan, X.J., Kieso, Y., Rossi, D., Gaidano, G., Chiorazzi, N., Ferrando, A.A., Dalla-Favera, R. Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 114(14):E2911-E2919, 2017