Platelets Enhance Multiple Myeloma Progression via IL-1β Upregulation
Platelets Enhance Multiple Myeloma Progression via IL-1β Upregulation
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DOI：
10.1158/1078-0432.ccr-17-2003
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发表时间：
2018-02
影响因子：
11.5
通讯作者：
S. Takagi;S. Tsukamoto;Jihye Park;Kelly E. Johnson;Y. Kawano;M. Moschetta;Chia-Jen Liu;Y. Mishima;K. Kokubun;S. Manier;K. Salem;D. Huynh;A. Sacco;J. Forward;A. Roccaro;E. Battinelli;I. Ghobrial
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文献类型：
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作者：
S. Takagi;S. Tsukamoto;Jihye Park;Kelly E. Johnson;Y. Kawano;M. Moschetta;Chia-Jen Liu;Y. Mishima;K. Kokubun;S. Manier;K. Salem;D. Huynh;A. Sacco;J. Forward;A. Roccaro;E. Battinelli;I. Ghobrial
目的：肿瘤细胞-血小板相互作用有助于实体瘤的进展和转移。然而，血小板在血液恶性肿瘤中的作用尚不清楚。我们研究了多发性骨髓瘤 (MM) 患者血小板活化状态与临床分期的关联，并探讨了血小板在 MM 进展中的作用。实验设计：血小板取自健康捐献者和多发性骨髓瘤患者。我们通过流式细胞术和透射电子显微镜检查了 MM 患者的血小板活化状态。我们还在血小板 RNA 测序中观察到与血小板激活相关的富集途径。 MM细胞系用于评估血小板对MM细胞体外增殖及其体内植入的影响。对 MM 细胞系进行 RNA 测序，以探索 MM 细胞-血小板相互作用的分子机制，并使用 CRISPR/Cas9 敲除方法进行验证。结果：随着疾病进展，多发性骨髓瘤患者的血小板高度激活。血小板 RNA 测序显示，冒烟型 MM (SMM) 或 MM 患者中与血小板相关的基因富集。血小板在体外促进MM细胞增殖，并在体内促进肿瘤在骨髓中的植入。 RNA测序显示，与血小板共培养的MM细胞系中IL-1β表达上调，而MM细胞系中IL-1β敲除消除了血小板对MM细胞增殖和体内植入的影响。结论：随着疾病进展，多发性骨髓瘤患者的血小板高度激活。 IL-1β 对于血小板介导的 MM 进展至关重要，可能是 MM 治疗的潜在靶点。临床癌症研究； 24（10）； 2430–9。 ©2018 AACR。
Purpose: Tumor cell–platelet interactions contribute to tumor progression and metastasis in solid tumors. However, the role of platelets in hematological malignancies is not clear. We investigated the association of platelet activation status with clinical stages in multiple myeloma (MM) patients and explored the role of platelets in MM progression. Experimental Design: Platelets were obtained from healthy donors and MM patients. We examined platelet activation status in MM patients by flow cytometry and transmission electron microscopy. We also observed the enriched pathways that are involved with platelet activation in RNA sequencing of platelets. MM cell lines were used to assess the effect of platelets on MM cell proliferation in vitro and their engraftment in vivo. RNA sequencing of MM cell lines was performed to explore molecular mechanisms underlying MM cell–platelet interaction and a CRISPR/Cas9 knockout approach was used for validation. Results: Platelets from MM patients were highly activated with disease progression. RNA sequencing of platelets revealed that genes involved in platelets were enriched in patients with smoldering MM (SMM) or MM. Platelets promoted MM cell proliferation in vitro and contributed to tumor engraftment in bone marrow in vivo. RNA sequencing revealed that IL-1β was upregulated in MM cell lines co-cultured with platelets, whereas IL-1β knockout in MM cell lines abrogated the effects of platelets on MM cell proliferation and engraftment in vivo. Conclusions: Platelets from MM patients were highly activated with disease progression. IL-1β is critical to platelet-mediated MM progression and might be a potential target for MM treatment. Clin Cancer Res; 24(10); 2430–9. ©2018 AACR.