Multiple myeloma is a plasma cell malignancy, which grows in the bone marrow (BM). The major population of cells in the BM is represented by neutrophils and they can form neutrophil extracellular traps (NET). Here, we investigated whether multiple myeloma cells induce NET formation and whether targeting this process would delay multiple myeloma progression. We demonstrated that murine and human multiple myeloma cells stimulate citrullination of histone H3 and NET formation by neutrophils and that this process is abrogated by pharmacological targeting of peptidylarginine deiminase 4 (PAD4) with a novel-specific small molecule inhibitor BMS-P5. Administration of BMS-P5 to multiple myeloma-bearing mice delays appearance of symptoms and disease progression. Taken together, our data demonstrate that targeting PAD4 may be beneficial for treatment of multiple myeloma.

中文翻译：

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一种新型肽基精氨酸脱亚胺酶 4 (PAD4) 抑制剂 BMS-P5 可阻断中性粒细胞胞外陷阱的形成并延缓多发性骨髓瘤的进展

多发性骨髓瘤是一种浆细胞恶性肿瘤，在骨髓 (BM) 中生长。BM 中的主要细胞群以中性粒细胞为代表，它们可以形成中性粒细胞胞外陷阱 (NET)。在这里，我们研究了多发性骨髓瘤细胞是否会诱导 NET 形成，以及针对这一过程是否会延迟多发性骨髓瘤的进展。我们证明了鼠和人多发性骨髓瘤细胞通过中性粒细胞刺激组蛋白 H3 的瓜氨酸化和 NET 形成，并且该过程被肽基精氨酸脱亚胺酶 4 (PAD4) 和新型特异性小分子抑制剂 BMS-P5 的药理学靶向所废除。对多发性骨髓瘤小鼠施用 BMS-P5 可延迟症状出现和疾病进展。综合起来，