Multiple myeloma is an incurable refractory hematologic malignancy arising from plasma cells in the bone marrow. Here we investigated miR-26a function in multiple myeloma and tested single-wall carbon nanotube delivery of miR-26a in vitro and in vivo. miR-26a was downregulated in patients with multiple myeloma cells compared with plasma cells from healthy donors. miR-26a overexpression inhibited proliferation and migration and induced apoptosis in multiple myeloma cell lines. To identify the targets of miR-26a, RPMI8226-V-miR-26-GFP and RPMI8226-V-GFP cells were cultured using stable isotope labeling by amino acids in cell culture (SILAC) medium, followed by mass spectrometry analysis. In multiple myeloma cells overexpressing miR-26a, CD38 protein was downregulated and subsequently confirmed to be a direct target of miR-26a. Depletion of CD38 in multiple myeloma cells duplicated the multiple myeloma inhibition observed with exogenous expression of miR-26a, whereas restoration of CD38 overcame the inhibition of miR-26a in multiple myeloma cells. In a human multiple myeloma xenograft mouse model, overexpression of miR-26a inhibited CD38 expression, provoked cell apoptosis, and inhibited cell proliferation. Daratumumab is the first CD38 antibody drug for monotherapy and combination therapy for patients with multiple myeloma, but eventually resistance develops. In multiple myeloma cells, CD38 remained at low level during daratumumab treatment, but a high-quality response is sustained. In daratumumab-resistant multiple myeloma cells, CD38 expression was completely restored but failed to correlate with daratumumab-induced cell death. Therefore, a therapeutic strategy to confer selection pressure to maintain low CD38 expression in multiple myeloma cells may have clinical benefit. SIGNIFICANCE: These results highlight the tumor suppressor function of miR-26a via its targeting of CD38 and suggest the therapeutic potential of miR-26a in patients with multiple myeloma.

中文翻译：

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肿瘤抑制物miR-26a对CD38的靶向作用是多发性骨髓瘤的新型潜在治疗剂。

多发性骨髓瘤是骨髓中浆细胞引起的顽固性难治性血液系统恶性肿瘤。在这里，我们研究了miR-26a在多发性骨髓瘤中的功能，并在体外和体内测试了miR-26a的单壁碳纳米管递送。与来自健康供体的浆细胞相比，在患有多发性骨髓瘤细胞的患者中miR-26a被下调。miR-26a过表达抑制多发性骨髓瘤细胞系的增殖和迁移并诱导凋亡。为了鉴定miR-26a的靶标，使用氨基酸在细胞培养（SILAC）培养基中进行稳定同位素标记，对RPMI8226-V-miR-26-GFP和RPMI8226-V-GFP细胞进行培养，然后进行质谱分析。在过度表达miR-26a的多发性骨髓瘤细胞中，CD38蛋白被下调，随后被证实是miR-26a的直接靶标。多发性骨髓瘤细胞中CD38的耗竭与miR-26a外源表达所观察到的多发性骨髓瘤抑制作用重复，而CD38的恢复克服了多发性骨髓瘤细胞中miR-26a的抑制作用。在人类多发性骨髓瘤异种移植小鼠模型中，miR-26a的过表达抑制CD38表达，引起细胞凋亡，并抑制细胞增殖。Daratumumab是首个用于多发性骨髓瘤患者的单一疗法和联合疗法的CD38抗体药物，但最终产生了耐药性。在多发性骨髓瘤细胞中，daratumumab治疗期间CD38仍处于较低水平，但仍可维持高质量应答。在耐daratumumab的多发性骨髓瘤细胞中，CD38表达已完全恢复，但与daratumumab诱导的细胞死亡无关。因此，赋予选择压力以维持多发性骨髓瘤细胞中CD38低表达的治疗策略可能具有临床益处。意义：这些结果突出了miR-26a通过靶向CD38的抑癌功能，并暗示了miR-26a在多发性骨髓瘤患者中的治疗潜力。