In this application, we propose to continue our on-going studies aimed at understanding the molecular pathogenesis and clinical behavior of DLLC, a clinically important subset of non-Hodgkin's lymphoma (NHL). The proposed studies have two aims.
One aim i s molecular analysis of a new class of chromosome aberration called promiscuous translocation. Promiscuously rearranging chromosomal sites participate in recurring translocations involving the IGH gene as well as other chromosomal sites suggesting that the candidate genes at these sites may be deregulated either by formation of chimeric gene products or by utilization of unrelated promoters. The following experimental goals will be pursued: (1) To isolate and characterize the candidate deregulated genes at the promiscuously rearranging chromosomal sites 1q21, 12p12, 12q24, and 15q13 through IGH-gene-associated rearrangements. (2). To molecularly characterize the rearrangements at the chromosomal sites which participate in non-14q32-associated translocation subsets involving the promiscuous translocation site 3q27/BCL6. The chromosomal sites targeted for this analysis will compromise: 1q21, 2q21, 4p11, and 5q13. A variety of cloning strategies including those based on IGH gene rearrangement, positional cloning, and identification of novel mRNA species fused 5' of mRNA of known rearranged genes by the RACE technique, will be utilized. The hypothesis underlying these studies is that analysis of normal and deregulated function of genes involved in such translocations will contribute to an understanding of the biology of DLLC.
A second aim of this application is to develop a genetic prognostic model for DLLC based on rearrangements affecting deregulated genes, amplification of specific genes, and copy number changes of chromosomal regions determined by the comparative genomic hybridization (CGH) technique. These genetic endpoints will be correlated with established clinical prognostic markers such as cell type and measures of bulk and extent of disease. A retrospective and a prospective analysis will be undertaken, the latter based on patients entered on the MSKCC Lymphoma protocol, NHL15M. The hypothesis underlying these studies is that the genetic basis of clinical outcome is complex and depends not only on deregulation of specific genes, but also on copy number changes of genes and chromosomal regions. The studies outlined will test the hypotheses proposed; they are a logical extension of our previous studies of DLLC and can be expected to lead to a better understanding of the biology and clinical behavior of this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA066999-04
Application #
2895265
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Jacobson, James W
Project Start
1996-06-06
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Cinti, Caterina; Macaluso, Marcella; Giordano, Antonio (2005) Tumor-specific exon 1 mutations could be the 'hit event' predisposing Rb2/p130 gene to epigenetic silencing in lung cancer. Oncogene 24:5821-6
Pasqualucci, Laura; Migliazza, Anna; Basso, Katia et al. (2003) Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 101:2914-23
Teruya-Feldstein, Julie; Donnelly, Gerard B; Goy, Andre et al. (2003) MUC-1 mucin protein expression in B-cell lymphomas. Appl Immunohistochem Mol Morphol 11:28-32
Nanjangud, Gouri; Rao, Pulivarthi H; Hegde, Abhijith et al. (2002) Spectral karyotyping identifies new rearrangements, translocations, and clinical associations in diffuse large B-cell lymphoma. Blood 99:2554-61
Palanisamy, Nallasivam; Abou-Elella, Ashraf A; Chaganti, Seeta R et al. (2002) Similar patterns of genomic alterations characterize primary mediastinal large-B-cell lymphoma and diffuse large-B-cell lymphoma. Genes Chromosomes Cancer 33:114-22
Mehra, Sukvarsha; Messner, Hans; Minden, Mark et al. (2002) Molecular cytogenetic characterization of non-Hodgkin lymphoma cell lines. Genes Chromosomes Cancer 33:225-34
Itoyama, Takahiro; Nanjungud, Gouri; Chen, Weiyi et al. (2002) Molecular cytogenetic analysis of genomic instability at the 1q12-22 chromosomal site in B-cell non-Hodgkin lymphoma. Genes Chromosomes Cancer 35:318-28
Chen, W; Itoyama, T; Chaganti, R S (2001) Splicing factor SRP20 is a novel partner of BCL6 in a t(3;6)(q27;p21) translocation in transformed follicular lymphoma. Genes Chromosomes Cancer 32:281-4
Chen, W; Palanisamy, N; Schmidt, H et al. (2001) Deregulation of FCGR2B expression by 1q21 rearrangements in follicular lymphomas. Oncogene 20:7686-93
Chaganti, R S; Nanjangud, G; Schmidt, H et al. (2000) Recurring chromosomal abnormalities in non-Hodgkin's lymphoma: biologic and clinical significance. Semin Hematol 37:396-411

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