多发性骨髓瘤（MM）是一种血液恶性肿瘤，其治愈率因患者反复复发和治疗耐药而受到极大挑战。我们之前提出 ADAM8、ADAM9 和 ADAM15（解整合素和金属蛋白酶 8/9/15）的高表达作为 MM 的不良预后标志物。本研究使用两个患者队列和七个人类 MM 细胞系 (HMCL) 重点研究了迄今为止很少研究的 ADAM8/9/15 在 MM 中的作用。 ADAM8/9/15 高表达与高风险细胞遗传学异常和髓外疾病相关。此外，与未经治疗的患者样本相比，ADAM8/15 表达随着 MM 进展而增加，在复发/难治性 MM 中也增加。比较 ADAM8/9/15high/low 患者样本的 RNA 测序和基因集富集分析显示，ADAM8/9/15high 患者样本中增殖标记物和增殖相关基因集上调。在患者组织的免疫组织化学染色中，高 ADAM8/9/15 表达与高 Ki67 相关，高 ADAM8/15 表达与高 MYC 蛋白表达相关。相反，HMCL 中 siRNA 介导的 ADAM8/9/15 敲除下调了增殖相关基因集。蛋白质印迹显示 ADAM8 敲低调节 IGF1R/AKT 信号传导，而 ADAM9 敲低则降低 mTOR 激活。最后，ADAM8/9/15 高表达水平被验证为独立于 Ki67/MYC 表达和/或高风险异常的预后标志物。总体而言，这些发现表明 ADAM8/9/15 在 MM 进展和增殖信号传导中发挥作用。© 2024。作者。

Multiple myeloma (MM) is a hematological malignancy whose curability is greatly challenged by recurrent patient relapses and therapy resistance. We have previously proposed the high expression of ADAM8, ADAM9 and ADAM15 (A Disintegrin And Metalloproteinase 8/9/15) as adverse prognostic markers in MM. This study focused on the so far scarcely researched role of ADAM8/9/15 in MM using two patient cohorts and seven human MM cell lines (HMCL). High ADAM8/9/15 expression was associated with high-risk cytogenetic abnormalities and extramedullary disease. Furthermore, ADAM8/15 expression increased with MM progression and in relapsed/refractory MM compared to untreated patient samples. RNA sequencing and gene set enrichment analysis comparing ADAM8/9/15high/low patient samples revealed an upregulation of proliferation markers and proliferation-associated gene sets in ADAM8/9/15high patient samples. High ADAM8/9/15 expression correlated with high Ki67 and high ADAM8/15 expression with high MYC protein expression in immunohistochemical stainings of patient tissue. Conversely, siRNA-mediated knockdown of ADAM8/9/15 in HMCL downregulated proliferation-related gene sets. Western blotting revealed that ADAM8 knockdown regulated IGF1R/AKT signaling and ADAM9 knockdown decreased mTOR activation. Lastly, high ADAM8/9/15 expression levels were verified as prognostic markers independent of Ki67/MYC expression and/or high-risk abnormalities. Overall, these findings suggest that ADAM8/9/15 play a role in MM progression and proliferation signaling.© 2024. The Author(s).