Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo.
Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo.
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DOI：
10.1038/leu.2015.124
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发表时间：
2015-11
期刊：
影响因子：
11.4
通讯作者：
Tassone P
中科院分区：
文献类型：
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作者：
Morelli E;Leone E;Cantafio ME;Di Martino MT;Amodio N;Biamonte L;Gullà A;Foresta U;Pitari MR;Botta C;Rossi M;Neri A;Munshi NC;Anderson KC;Tagliaferri P;Tassone P
干扰素调节因子 4 (IRF4) 是多发性骨髓瘤 (MM) 的一个有吸引力的治疗靶点。我们在此报告，MM 患者中 IRF4 mRNA 的表达与 microRNA (miR)-125b 呈负相关。此外，我们提供的证据表明 miR-125b 在 TC2/3 分子 MM 亚组和已建立的细胞系中下调。重要的是，慢病毒载体或合成模拟物转染的miR-125b-5p组成型表达损害了MM细胞的生长和存活，并克服了体外骨髓基质细胞的保护作用。 MM 细胞中 miR-125b-5p 异位表达引发细胞凋亡和自噬相关的细胞死亡。重要的是，我们发现 miR-125b-5p 的抗 MM 活性是通过直接下调 IRF4 及其下游效应子 BLIMP-1 介导的。此外，IRF4 的抑制转化为相关 IRF4 下游效应子 c-Myc、caspase-10 和 cFlip 的下调。最后，在严重联合免疫缺陷/非肥胖糖尿病小鼠中，体内肿瘤内或全身递送针对人MM异种移植物的配制的miR-125b-5p模拟物诱导了显着的抗肿瘤活性并延长了生存期。总而言之，我们的研究结果提供了证据，表明 miR-125b 与其他血液恶性肿瘤不同，在 MM 中具有肿瘤抑制活性。此外，我们的数据提供了概念证明，即合成的 miR-125b-5p 模拟物是有希望在早期临床试验中得到验证的抗 MM 药物。
Interferon regulatory factor 4 (IRF4) is an attractive therapeutic target in multiple myeloma (MM). We here report that expression of IRF4 mRNA inversely correlates with microRNA (miR)-125b in MM patients. Moreover, we provide evidence that miR-125b is downregulated in TC2/3 molecular MM subgroups and in established cell lines. Importantly, constitutive expression of miR-125b-5p by lentiviral vectors or transfection with synthetic mimics impaired growth and survival of MM cells and overcame the protective role of bone marrow stromal cells in vitro. Apoptotic and autophagy-associated cell death were triggered in MM cells on miR-125b-5p ectopic expression. Importantly, we found that the anti-MM activity of miR-125b-5p was mediated via direct downregulation of IRF4 and its downstream effector BLIMP-1. Moreover, inhibition of IRF4 translated into downregulation of c-Myc, caspase-10 and cFlip, relevant IRF4-downstream effectors. Finally, in vivo intra-tumor or systemic delivery of formulated miR-125b-5p mimics against human MM xenografts in severe combined immunodeficient/non-obese diabetic mice induced significant anti-tumor activity and prolonged survival. Taken together, our findings provide evidence that miR-125b, differently from other hematologic malignancies, has tumor-suppressor activity in MM. Furthermore, our data provide proof-of-concept that synthetic miR-125b-5p mimics are promising anti-MM agents to be validated in early clinical trials.