Lenalidomide efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and cereblon expression
Lenalidomide efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and cereblon expression
复制标题
DOI：
10.1111/bjh.12172
复制
发表时间：
2013-02-01
影响因子：
6.5
通讯作者：
Chopra, Rajesh
中科院分区：
文献类型：
--
作者：
Zhang, Ling-Hua;Kosek, Jolanta;Chopra, Rajesh
来那度胺单一疗法在非霍奇金淋巴瘤患者中有持久疗效的报道。在复发/难治性弥漫性大B细胞淋巴瘤(DLBCL)中，激活的B细胞样(ABC)亚型的应答高于生发中心B细胞样亚型。本研究旨在探讨来那度胺对DLBCL亚型疗效差异性的分子机制。利用DLBCL细胞系，来那度胺在体外优先抑制ABC-DLBCL细胞的增殖，并在人肿瘤异种移植模型中延缓肿瘤的生长，而对非ABC-DLBCL细胞的影响最小。这种杀瘤作用与干扰素调节因子4(IRF4)的下调有关，IRF4是ABC-DLBCL细胞的标志。来那度胺抑制IRF4诱导B细胞受体(BCR)依赖的NF-B表达下调，而IRF4特异的小干扰RNA模拟来那度胺降低NF-B激活的作用，IRF4过表达增强了NF-B的激活并增强了对来那度胺的耐药性。这些发现表明，抑制IRF4在来那度胺对ABC细胞的疗效中起着至关重要的作用。此外，来那度胺诱导的IRF4下调需要来那度胺的分子靶点雷公藤蛋白的表达。综上所述，这些发现表明来那度胺对DLBCL细胞，尤其是ABC-DLBCL细胞具有直接的抗肿瘤活性，其机制是通过阻断IRF4的表达和bcr-nf-？b信号通路而实现的。
Durable responses with lenalidomide monotherapy have been reported in patients with non-Hodgkin lymphoma. In relapsed/refractory diffuse large B-cell lymphoma (DLBCL), higher responses were observed in the activated B-cell-like (ABC) subtype than in the germinal centre B-cell-like subtype. Herein, the molecular mechanisms involved in the differential efficacy of lenalidomide in DLBCL subtypes were investigated. Using DLBCL cell lines, lenalidomide treatment was found to preferentially suppress proliferation of ABC-DLBCL cells in vitro and delay tumour growth in a human tumour xenograft model, with minimal effect on non-ABC-DLBCL cells. This tumouricidal effect was associated with downregulation of interferon regulatory factor 4 (IRF4), a hallmark of ABC-DLBCL cells. IRF4 inhibition by lenalidomide induced downregulation of B-cell receptor (BCR)-dependent NF-?B. Whereas IRF4-specific small, interfering RNA mimicked the effects of lenalidomide reducing NF-?B activation, IRF4 overexpression enhanced NF-?B activation and conferred resistance to lenalidomide. These findings indicate the crucial role of IRF4 inhibition in lenalidomide efficacy in ABC cells. Furthermore, lenalidomide-induced IRF4 downregulation required the expression of cereblon, a molecular target of lenalidomide. Taken together, these findings suggest that lenalidomide has direct antitumour activity against DLBCL cells, preferentially ABC-DLBCL cells, by blocking IRF4 expression and the BCR-NF-?B signalling pathway in a cereblon-dependent manner.