Wong David, Winter Oliver, Hartig Christina, Siebels Svenja, Szyska Martin, Tiburzy Benjamin, Meng Lingzhang, Kulkarni Upasana, Fähnrich Anke, Bommert Kurt, Bargou Ralf, Berek Claudia, Chu Van Trung, Bogen Bjarne, Jundt Franziska, Manz Rudolf Armin
University of Lübeck, Institute for Systemic Inflammation Research, ISEF, Lübeck, Germany.
Charité - University Medicine Berlin, Department of Rheumatology and German Arthritis Research Center DRFZ, Berlin, Germany.
PLoS One. 2014 Oct 1;9(10):e109018. doi: 10.1371/journal.pone.0109018. eCollection 2014.
Multiple myeloma is a bone marrow plasma cell tumor which is supported by the external growth factors APRIL and IL-6, among others. Recently, we identified eosinophils and megakaryocytes to be functional components of the micro-environmental niches of benign bone marrow plasma cells and to be important local sources of these cytokines. Here, we investigated whether eosinophils and megakaryocytes also support the growth of tumor plasma cells in the MOPC315.BM model for multiple myeloma. As it was shown for benign plasma cells and multiple myeloma cells, IL-6 and APRIL also supported MOPC315.BM cell growth in vitro, IL-5 had no effect. Depletion of eosinophils in vivo by IL-5 blockade led to a reduction of the early myeloma load. Consistent with this, myeloma growth in early stages was retarded in eosinophil-deficient ΔdblGATA-1 mice. Late myeloma stages were unaffected, possibly due to megakaryocytes compensating for the loss of eosinophils, since megakaryocytes were found to be in contact with myeloma cells in vivo and supported myeloma growth in vitro. We conclude that eosinophils and megakaryocytes in the niches for benign bone marrow plasma cells support the growth of malignant plasma cells. Further investigations are required to test whether perturbation of these niches represents a potential strategy for the treatment of multiple myeloma.
多发性骨髓瘤是一种骨髓浆细胞瘤,其生长受到多种外部生长因子的支持,如增殖诱导配体(APRIL)和白细胞介素-6(IL-6)等。最近,我们发现嗜酸性粒细胞和巨核细胞是良性骨髓浆细胞微环境龛的功能组成部分,并且是这些细胞因子的重要局部来源。在此,我们研究了在多发性骨髓瘤的MOPC315.BM模型中,嗜酸性粒细胞和巨核细胞是否也支持肿瘤浆细胞的生长。正如在良性浆细胞和多发性骨髓瘤细胞中所显示的那样,IL-6和APRIL在体外也支持MOPC315.BM细胞的生长,而IL-5则没有作用。通过IL-5阻断在体内耗尽嗜酸性粒细胞导致早期骨髓瘤负荷降低。与此一致的是,在嗜酸性粒细胞缺陷的ΔdblGATA-1小鼠中,早期骨髓瘤的生长受到抑制。晚期骨髓瘤阶段未受影响,这可能是由于巨核细胞补偿了嗜酸性粒细胞的损失,因为在体内发现巨核细胞与骨髓瘤细胞接触并且在体外支持骨髓瘤生长。我们得出结论,良性骨髓浆细胞龛中的嗜酸性粒细胞和巨核细胞支持恶性浆细胞的生长。需要进一步研究来测试扰乱这些龛是否代表治疗多发性骨髓瘤的潜在策略。