title: IL-21 in the bone marrow microenvironment contributes to IgM secretion and proliferation of malignant cells in Waldenstrom macroglobulinemia.
abstract: Cytokines within the tumor microenvironment play an important role in supporting the growth and survival of B-cell malignancies. One such cytokine, IL-21, promotes the growth of myeloma and Hodgkin lymphoma cells while inducing apoptosis in chronic lymphocytic leukemia. However, the biologic significance of IL-21 has not been examined in Waldenstrom macroglobulinemia (WM), a B-cell lymphoma characterized by elevated serum IgM and a lymphoplasmacytic bone marrow infiltrate. We report here on the presence of IL-21 in the bone marrow of patients with WM and have identified activated T cells as the source of this cytokine. We readily detected the IL-21 receptor on malignant WM B cells and show that IL-21 significantly increases both IgM secretion and cellular proliferation of these cells with no effect on viability. IL-21 rapidly induces phosphorylation of STAT3 in WM cells, and treatment of the WM cell line MWCL-1 with a STAT3 inhibitor abolished the IL-21-mediated increases in cellular proliferation and IgM secretion. IL-21 also increased the expression of known STAT3 targets involved in B-cell differentiation, including BLIMP-1, XBP-1, IL-6, and IL-10. Overall, our data indicate that IL-21 in the bone marrow microenvironment significantly affects the biology of WM tumor cells through a STAT3-dependent mechanism.
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Lucy S
authors.initials: LS
authors.lastname: Hodge
authors.forename: Steve C
authors.initials: SC
authors.lastname: Ziesmer
authors.forename: Zhi Zhang
authors.initials: ZZ
authors.lastname: Yang
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Secreto
authors.forename: Morie A
authors.initials: MA
authors.lastname: Gertz
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
mesh_terms: D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000276:immunology; D007150:Immunohistochemistry; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology*; D008258:Waldenstrom Macroglobulinemia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D000098546:Interleukin-21
chemical_list: D007075:Immunoglobulin M; D007378:Interleukins; D000098546:Interleukin-21