Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Blood. 2012 Nov 1;120(18):3774-82. doi: 10.1182/blood-2012-03-419440. Epub 2012 Sep 13.
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.
肿瘤微环境中的细胞因子在支持 B 细胞恶性肿瘤的生长和存活方面发挥着重要作用。其中一种细胞因子，白细胞介素 21（IL-21），促进骨髓瘤和霍奇金淋巴瘤细胞的生长，同时诱导慢性淋巴细胞白血病细胞凋亡。然而，白细胞介素 21 在 Waldenstrom 巨球蛋白血症（WM）中的生物学意义尚未被研究，WM 是一种 B 细胞淋巴瘤，其特征是血清 IgM 升高和淋巴浆细胞性骨髓浸润。我们在这里报告了白细胞介素 21 存在于 WM 患者的骨髓中，并确定活化的 T 细胞是这种细胞因子的来源。我们很容易在恶性 WM B 细胞上检测到白细胞介素 21 受体，并表明白细胞介素 21 显著增加这些细胞的 IgM 分泌和细胞增殖，而对细胞活力没有影响。白细胞介素 21 可迅速诱导 WM 细胞中 STAT3 的磷酸化，用 STAT3 抑制剂处理 WM 细胞系 MWCL-1 可消除白细胞介素 21 介导的细胞增殖和 IgM 分泌增加。白细胞介素 21 还增加了已知参与 B 细胞分化的 STAT3 靶基因的表达，包括 BLIMP-1、XBP-1、IL-6 和 IL-10。总体而言，我们的数据表明，骨髓微环境中的白细胞介素 21 通过 STAT3 依赖性机制显著影响 WM 肿瘤细胞的生物学特性。
