The focus of this project is, a deeper understanding of the early development of the B-cell lineage in the bursa of Fabricius, and the perturbation of that development during induction of malignant lymphomas in the bursa by deregulated expression of the c-myc oncogene. Using a variety of experimental approaches including retroviral vector-mediated gene transfer into bursal stem cells and bursal transplantation, targeted gene deletion/replacement in a bursal lymphoma-derived cell line (DT-40) and microarray analysis, we propose to focus on three groups of specific aims. First our chicken immune system microarray will be expanded, and modifications made to our retroviral vectors in order to detect changes in gene expression associated with progression from preneoplastic to fully neoplastic stages of lymphomagenesis. With this approach the hypothesis that myb-induced bursal lymphomas involve deregulation of c-myc will be tested. Expression profiles of myc-, myb- and v-rel-induced bursal lymphomas will be compared to seek evidence of a common pathway of lymphomagenesis. We will explore the role of the novel anti-apoptotic regulator Nr-13, and the pro-apoptotic protein Mtd/Bok. These relatively little-investigated genes are candidates to be major regulators of the intense apoptosis which accompanies normal B-cell development in the bursa and which is significantly modified during myc-induced neoplastic development. Therefore, second, DT-40 cells deleted for Nr-13 will be analyzed to determine whether it is essential for viability, and a mutational analysis will be carried out to identify domains required for several functions of Nr-13 including the ability of Nr-13 to maintain bursal stem cell function in vivo. Third, We will determine the intracellular localization of two naturally occurring forms of Mtd/Bok, and define the anti-apoptotic proteins with which it/they interact. Testing of the effects of constitutive overexpression of these proteins in bursal stem cell on normal and neoplastic B-cell development will reveal whether a block to apoptosis induced by Mtd/Bok exists and plays a role in tumor progression. Finally dominant inhibitors of Mtd/Bok function will be tested probe the role of this gene in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA020068-28
Application #
6839403
Study Section
Special Emphasis Panel (ZRG1-PTHC (01))
Program Officer
Cole, John S
Project Start
1976-03-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
28
Fiscal Year
2005
Total Cost
$346,433
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Neiman, Paul E; Elsaesser, Katrina; Loring, Gilbert et al. (2008) Myc oncogene-induced genomic instability: DNA palindromes in bursal lymphomagenesis. PLoS Genet 4:e1000132
Kimmel, Robert R; Agnani, Shivali; Yang, Yin et al. (2008) DNA copy-number instability in low-dose gamma-irradiated TK6 lymphoblastoid clones. Radiat Res 169:259-69
Kimmel, Robert R; Zhao, Lue Ping; Nguyen, Doan et al. (2006) Microarray comparative genomic hybridization reveals genome-wide patterns of DNA gains and losses in post-Chernobyl thyroid cancer. Radiat Res 166:519-31
Neiman, P E; Kimmel, R; Icreverzi, A et al. (2006) Genomic instability during Myc-induced lymphomagenesis in the bursa of Fabricius. Oncogene 25:6325-35
Neiman, Paul E; Burnside, Joan; Elsaesser, Katrina et al. (2006) Analysis of gene expression, copy number and palindrome formation with a Dt40 enriched cDNA microarray. Subcell Biochem 40:245-56
Burnside, Joan; Neiman, Paul; Tang, Jianshan et al. (2005) Development of a cDNA array for chicken gene expression analysis. BMC Genomics 6:13
Brown, Cheryl Y; Bowers, Sandra J; Loring, Gibert et al. (2004) Role of Mtd/Bok in normal and neoplastic B-cell development in the bursa of Fabricius. Dev Comp Immunol 28:619-34
Parghi, Sean S; Brandvold, Kimberly A; Bowers, Sandra J et al. (2004) Reduced Myc overexpression and normal B-cell differentiation mediate resistance to avian leukosis virus lymphomagenesis. Oncogene 23:4413-21
Black, Elizabeth J; Clair, Timothy; Delrow, Jeffrey et al. (2004) Microarray analysis identifies Autotaxin, a tumour cell motility and angiogenic factor with lysophospholipase D activity, as a specific target of cell transformation by v-Jun. Oncogene 23:2357-66
Cheng, Chun; Kimmel, Robert; Neiman, Paul et al. (2003) Array rank order regression analysis for the detection of gene copy-number changes in human cancer. Genomics 82:122-9

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