Multiple myeloma is a universally fatal disease characterized by the accumulation of malignant plasma cells in the bone marrow. The growth characteristics of myeloma cells are in striking contrast with those of normal end-stage plasma cells. The molecular regulation of normal B cell terminal differentiation is incompletely understood, however, it is believed that this regulation involves the activation of transcription factors that are necessary to drive expression of genes whose products are specific to the differentiated phenotype. Interleukin 6 (IL-6) is an important example of an external signal that drives normal B cell differentiation; however, it does so in the absence of any effect on cell growth. In contrast, IL-6 functions as a potent growth factor for malignant plasma cells in patients with aggressive myeloma. We have, therefore, hypothesized that myeloma cells display an altered responsiveness to IL-6, i.e., growth rather than differentiation, and as a result of this IL-6 responsiveness, there are key changes in IL-6-stimulated gene expression. Considerable information exists regarding IL-6-mediated activation of the JAK/STAT and Ras-MAP kinase (Ras-MAPK) pathways, however, the role of either pathway has not been established in IL-6 mediated myeloma cell growth. The Pi previously has established a panel of IL-6-responsive human myeloma cell lines and also has significant expertise in the study of normal human B cells and plasmablasts. She is, therefore, uniquely positioned to analyze the role of these well-characterized signaling pathways in myeloma cell growth.
The specific aims i nclude: (l) to determine the importance of the JAK/STAT activation pathway in IL-6 driven myeloma cell proliferation; (2) to determine the importance of the Ras/MAPK activation pathway in IL-6 driven myeloma cell proliferation; and (3) to identify and characterize the genetic targets of IL-6 signal transduction pathway(s) in myeloma by utilizing differential display reverse transcription polymerase chain reaction and cDNA array analysis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA062242-07
Application #
6416229
Study Section
Subcommittee E - Prevention &Control (NCI)
Project Start
2001-02-01
Project End
2002-01-31
Budget Start
Budget End
Support Year
7
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Lwin, S T; Fowler, J A; Drake, M T et al. (2017) A loss of host-derived MMP-7 promotes myeloma growth and osteolytic bone disease in vivo. Mol Cancer 16:49
Gonsalves, W I; Rajkumar, S V; Dispenzieri, A et al. (2017) Quantification of circulating clonal plasma cells via multiparametric flow cytometry identifies patients with smoldering multiple myeloma at high risk of progression. Leukemia 31:130-135
Mullikin, Trey C; Rajkumar, S Vincent; Dispenzieri, Angela et al. (2016) Clinical characteristics and outcomes in biclonal gammopathies. Am J Hematol 91:473-5
Gonsalves, Wilson I; Timm, Michael M; Rajkumar, S Vincent et al. (2016) The prognostic significance of CD45 expression by clonal bone marrow plasma cells in patients with newly diagnosed multiple myeloma. Leuk Res 44:32-9
Kaufman, Gregory P; Dispenzieri, Angela; Gertz, Morie A et al. (2015) Kinetics of organ response and survival following normalization of the serum free light chain ratio in AL amyloidosis. Am J Hematol 90:181-6
Gonsalves, W I; Leung, N; Rajkumar, S V et al. (2015) Improvement in renal function and its impact on survival in patients with newly diagnosed multiple myeloma. Blood Cancer J 5:e296
Teoh, P J; Chung, T H; Sebastian, S et al. (2014) p53 haploinsufficiency and functional abnormalities in multiple myeloma. Leukemia 28:2066-74
Gonsalves, Wilson I; Morice, William G; Rajkumar, Vincent et al. (2014) Quantification of clonal circulating plasma cells in relapsed multiple myeloma. Br J Haematol 167:500-5
Greenberg, A J; Rajkumar, S V; Therneau, T M et al. (2014) Relationship between initial clinical presentation and the molecular cytogenetic classification of myeloma. Leukemia 28:398-403
Gonsalves, W I; Rajkumar, S V; Gupta, V et al. (2014) Quantification of clonal circulating plasma cells in newly diagnosed multiple myeloma: implications for redefining high-risk myeloma. Leukemia 28:2060-5

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