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.
Selected
Publications
Niu, H., Ye, B-H., and Dalla-Favera, R. Antigen-Receptor Signaling
Induces MAP Kinase-Mediated Phosphorylation and Degradation of the BCL-6
Transcription Factor. Genes & Dev., 12(13): 1953-1961 (1998).
Pasqualucci, L., Migliazza, A., Fracchiolla N., William C., Neri, A.,
Baldini, L., Chaganti, R.S.K., Klein, U., Kueppers, R., Rajewsky, K.,
Dalla-Favera, R. BCL-6 mutations in normal germinal center B cells:
Evidence of somatic hypermutation acting outside Ig loci. Proc Natl Acad
Sci (USA), 95: 11816-11821, (1998).
Wu, K.-J., Dalla-Favera, R. Direct activation of telomerase reverse
transcriptase (hTERT) gene transcription by c-MYC. Nature Genetics, 21:
220-224 (1999). Wu, K-J., Polack, A., Dalla-Favera, R. (1999).
Wu, K.-J., Polack, A., Dalla-Favera, R. Coordinated regulation of
iron-controlling genes, H-Ferritin and IRP2, by c-Myc. Science, 283:
676-679 (1999).
Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS,
Kuppers R, Dalla-Favera R. Hypermutation of multiple proto-oncogenes in
B-cell diffuse large-cell lymphomas. Nature, 19:341-346 (2001).
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., Dalla-Favera, R. Gene expression profiling of B cell
chronic lymphocytic leukemia reveals a homogenous phenotype related to
memory B cells. J. Exp Med, 97: 2098-2104 (2001) (Supplementary Data)
Klein, U., Gloghini, A., Gaidano, G., Chadburn, A., Cesarman, E.,
Dalla-Favera, R., Carbone, A. Gene expression profile analysis of
AIDS-related primary effusion lymphoma (PEL) suggests a plasmablastic
derivation and identifies PEL-specific transcripts. Blood First Edition
Paper, prepublished online January 16, 2003 (Supplementary Data)
Klein, U., Tu, Y., Stolovitzky, G.A.,
Keller, J.L., Haddad Jr., J., Miljkovic, V., Cattoretti, G., Califano,
A., Dalla-Favera, R. Transcriptional Analysis of the B-Cell Germinal
Center Reaction. Proc. Acad. Natl. Sci. U. S. A. 100:2639-2644, 2003 (Supplementary Data)
Küppers, R., U. Klein, I. Schwering, V.
Distler, A. Bräuninger, G. Cattoretti, Y. Tu, G.A. Stolovitzky, A.
Califano, M.-L. Hansmann, and R. Dalla-Favera. Identification of Hodgkin
and Reed-Sternberg Cell-Specific Genes by Gene Expression Profiling. J.
Clin. Invest. 111:529-537, 2003
(Supplementary Data)
Basso,
K., Liso, A., Tiacci, E., Benedetti, R., Pulsoni, A., Foa, R., Di
Raimondo, F., Ambrosetti, A., Califano, A., Klein, U., Dalla-Favera, R.,
Falini, B. Gene expression profiling of hairy cell leukemia reveals a
phenotype related to memory B cells with altered expression of chemokine
and adhesion receptors. J. Exp. Med. 199 (1):
59-68. (Supplementary
Data)
Basso, K., Klein, U.,
Niu, H., Stolovitzky G.A., Tu, Y., Califano, A., Cattoretti, G., and
Dalla-Favera, R. Tracking CD40 signaling during germinal center
development Blood 104 (13): 4088-4096 2004. (Supplementary Data)
