Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition and its frequency increases dramatically with age: 1% of adults over 25, 3% of those over 50, and 20% of those over 90. It is reported to progress to multiple myeloma (MM) at a rate of 2% per year. Both conditions are more prevalent in men than in women, and in blacks compared to whites. We have shown that MM is characterized by frequent chromosome translocations involving the immunoglobulin (Ig) genes and hyperdiploidy. These appear to be primary genetic events, and in all cases associated with dysregulated expression of a cyclin D gene, providing a universal basis for the development of MGUS and MM. The only known genetic factors associated with progression from MGUS to MM are activating mutations of RAS, and rearrangements of MYC, however their causative role, if any, in the MGUS-MM transition has not been proven yet given the difficulty of performing biological studies on primary MM patient cells. We propose to use the genetically engineered Vk*MYC mice to study the biologic factors underlying the development and progression of MGUS. During the last funding cycle we confirmed that aging C57BL/6, but not CBA or BALB/c mice spontaneously develop MGUS. We showed that sporadic activation of a MYC transgene in individual germinal center B-cells in C57BL/6 Vk*MYC mice universally converted this phenotype to one of progressive MM, indicating a causative role for MYC dysregulation in the progression of MGUS to MM. Using a combination of high throughput technologies, including gene expression profiling and aCGH, on primary MGUS and MM tumors arising in Vk*MYC mice we will identify the genetic changes associated with tumor progression from MGUS to intra- and extra-medullary MM. Furthermore, we will take advantage of our ability to serially transplant these MM tumors in syngeneic mice to study the biology of MM cells in vivo, focusing on genetic factors in tumor progression. Finally, using novel transgenic mice, we will functionally study the role of activation of RAS and dysregulation of cyclin D1 in the progression of MGUS to MM. In summary, by taking advantage of our unique and highly innovative mouse model of MM, will address fundamental questions concerning the susceptibility to one of the commonest age- associated pre-malignant conditions, the nature of tumor stem cells, and the genetics of multi-step tumor progression. The results will have important implications for the prognosis, prevention and treatment of individuals with MGUS, patients with MM, and cancer patients generally.
Project Narrative Monoclonal gammopathy of undetermined significance is one of the most common age-associated pre- malignant conditions in man. This project will use genetically engineered mice to dissect the mechanisms of disease susceptibility, biology and progression, performing studies that cannot be done in man, but with direct relevance to the human disease.
|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|
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