A striking clinical feature of myeloma cells relates to their tendency to remain in the bone marrow environment until the very end stage of the disease. Although several of the molecules important in myeloma cell- stromal cell adhesion have been identified, little is known about the factors that regulate adhesion molecule expression/function in human myeloma cells. Because we have shown that IL-1beta is abnormally produced in virtually all myeloma patients and because IL-1beta has been shown to upregu1ate adhesion molecules in other cellular systems, we propose to investigate the role of IL-1beta on adhesion molecule expression and function. We hypothesize that the aberrant IL-1beta production upregulates adhesion molecules on either the myeloma cells or the marrow stromal cells, or both, and induces increased myeloma cell-stroma1 cell adhesion and paracrine IL-6 production. Using human myeloma cell lines, that differ with respect to IL-1beta expression in the SCID mouse model that mimics human disease, and freshly isolated bone marrow cells from patients with MGUS and MM to test this hypothesis, we propose to: 1) Study the in vivo effects of IL-1beta sense/antisense cDNAs on human myeloma cell lines in the SCID mouse model; 2) Determine the adhesion molecule phenotype of IL-1beta positive and negative plasma cells from patients with MGUS or myeloma and investigate the effects of IL-1beta, anti-IL-1beta antibody, soluble IL-1 receptors, IL-1 receptor antagonist, or an interleukin- 1beta converting enzyme (ICE) chemical inhibitor on the adhesion molecule expression of myeloma cells from patients; 3) Investigate the effects of IL- 1beta, anti-IL-1beta antibody, soluble IL-I receptors, IL- l receptor antagonist, or an ICE chemical inhibitor on the adhesion of patient myeloma cells to bone marrow stromal cells and on IL-6 production. Collectively, these proposed experiments will provide critical information in myeloma toward the understanding of the role of IL-1beta in adhesion molecule expression/function and disease pathology.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Subcommittee E - Prevention &Control (NCI)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
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
Gonsalves, Wilson I; Rajkumar, S Vincent; Go, Ronald S et al. (2014) Trends in survival of patients with primary plasma cell leukemia: a population-based analysis. Blood 124:907-12
Wong, Tina W; Doyle, Alfred D; Lee, James J et al. (2014) Eosinophils regulate peripheral B cell numbers in both mice and humans. J Immunol 192:3548-58
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

Showing the most recent 10 out of 365 publications