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

The development of many types of cancer is due to genetic lesions involving proto-oncogenes and tumor suppressor genes. It is well established that multiple lesions must occur in a cell before cancer can develop. The general goal of this laboratory is to identify the lesions and the genes involved in the development of human B cell lymphoma, to determine the mechanism by which these lesions occur and to elucidate the contribution of each lesion to tumor development. Specific lines of investigation include:

1) Elucidating the role of chromosomal translocations involving the c-myc proto oncogene locus and immuno-globulin loci in the development of Burkitt's lymphoma. These studies include the analysis of the mechanisms regulating the expression of the normal c-myc gene as well as of c-myc alleles structurally altered by chromosomal translocation in lymphoma cells.

2) Studying the normal and pathologic function of the BCL-6 gene, a recently identified proto-oncogene which codes for a transcription factor expressed in B cells and is altered in its regulatory region in a significant fraction of human lymphoma.

3) Identifying novel oncogenes and tumor suppressors involved in the pathogenesis of lymphoma by virtue of their involvement in tumor-associated chromosomal translocations or by "positional cloning" from chromosomal regions involved in tumor-associated deletions.

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1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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. Nat Genet. 40: 108-112.
7. 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. Nat Immunol. 8: 1132-1139.
8. 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.
9. 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.
10. 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.
11. Phan, R.T., Saito, M., Basso, K., Niu, H. and Dalla-Favera, R. (2005) BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cells. Nat Immunol. 6: 1054-1060.
12. Cattoretti, G., Pasqualucci, L., Ballon, G., Tam, W., Nandula, S.V., Shen, Q., Mo, T., Murty, V.V. and Dalla-Favera, R. (2005) Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B-cell lymphomas in mice. Cancer Cell 7: 445-455.
13. Phan, R.T. and Dalla-Favera, R. (2004) The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432: 635-639.
14. Bereshchenko, O.R., Gu, W. and Dalla-Favera, R. (2002) Acetylation inactivates the transcriptional repressor BCL6. Nat Genet. 32: 606-613.