Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition and its frequency increases dramatically with age: 1% of adults over 25, 2% of those over 50, and 20% of those over 90. It is reported to progress to multiple myeloma (MM) at a rate of 1% per year. Recently we have shown that multiple myeloma is characterized by frequent (70%) chromosome translocations involving the immunoglobulin (Ig) genes and identified four recurrent loci that are commonly involved: 11q13, 6p21, 4p16, and 16q23. The translocations result in the juxtaposition of powerful Ig enhancers adjacent to oncogenes at these loci (cyclin D1, cyclin D3, FGFR3+MMSET, and c-maf, respectively), causing their ectopic and deregulated expression in plasma cells. Using interphase FISH, IgH translocations are detected with a similar frequency in the pre-malignant MGUS. When present, they are present in every clonal cell, indicating that the translocation event precedes the clonal expansion. We hypothesize that the ectopic expression of oncogenes, as a result of IgH translocation, is the first step in the development of these clonal plasma cell expansions. We propose to study MGUS that occurs spontaneously in aging mice, develop a murine model for the generation of antigen-specific MGUS, and study the B cell clones that produce them. Such a model will allow us to isolate the cells responsible for the MGUS and study alterations in their phenotype or genotype. We will determine if these expansions share similar ectopic gene expression, evidence of numerical chromosomal abnormalities, or immunoglobulin gene translocation. We will determine the role of ongoing antigen exposure in maintaining the clone's large size. Finally, we propose to create transgenic mice in which the expression of the relevant oncogenes is controlled by Ig regulatory elements, mimicking the effect of the Ig translocation. These studies will allow us to define the role of these genetic abnormalities in the development of plasma cell neoplasms. They also provide a framework to identify and study the contribution of additional events involved in the initiation and progression of MGUS and MM.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020686-04
Application #
7096673
Study Section
Special Emphasis Panel (ZRG1-CAMP (01))
Program Officer
Fuldner, Rebecca A
Project Start
2003-05-15
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$305,415
Indirect Cost
Name
Mayo Clinic, Arizona
Department
Type
DUNS #
153665211
City
Scottsdale
State
AZ
Country
United States
Zip Code
85259
Schuster, Steven R; Kortuem, K Martin; Zhu, Yuan Xiao et al. (2014) The clinical significance of cereblon expression in multiple myeloma. Leuk Res 38:23-8
Grover, Rajesh K; Zhu, Xueyong; Nieusma, Travis et al. (2014) A structurally distinct human mycoplasma protein that generically blocks antigen-antibody union. Science 343:656-661
Tanno, Toshihiko; Lim, Yiting; Wang, Qiuju et al. (2014) Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells. Blood 123:725-33
Bergsagel, P Leif; Mateos, Maria-Victoria; Gutierrez, Norma C et al. (2013) Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood 121:884-92
Dispenzieri, Angela; Stewart, A Keith; Chanan-Khan, Asher et al. (2013) Smoldering multiple myeloma requiring treatment: time for a new definition? Blood 122:4172-81
Bergsagel, P Leif; Chesi, Marta (2013) V. Molecular classification and risk stratification of myeloma. Hematol Oncol 31 Suppl 1:38-41
Schmidt, J; Braggio, E; Kortuem, K M et al. (2013) Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia 27:2357-65
Matthews, G M; Lefebure, M; Doyle, M A et al. (2013) Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma. Cell Death Dis 4:e798
Bergsagel, P L; Kuehl, W M (2013) Degree of focal immunoglobulin heavy chain locus deletion as a measure of B-cell tumor purity. Leukemia 27:2067-8
De, Pradip; Dey, Nandini; Terakedis, Breanne et al. (2013) An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo. Cancer Chemother Pharmacol 71:867-81

Showing the most recent 10 out of 47 publications