IRF4 addiction in multiple myeloma
IRF4 addiction in multiple myeloma
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DOI：
10.1038/nature07064
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发表时间：
2008-07-10
期刊：
影响因子：
64.8
通讯作者：
Staudt, Louis M.
中科院分区：
文献类型：
--
作者：
Shaffer, Arthur L.;Emre, N. C. Tolga;Staudt, Louis M.
转录因子IRF 4（干扰素调节因子4）在免疫应答期间是淋巴细胞活化和产生免疫球蛋白分泌浆细胞所必需的（1-3）。多发性骨髓瘤是一种浆细胞恶性肿瘤，具有复杂的分子病因学，通过基因表达谱和复发性染色体易位定义了几个亚组（4，5）。此外，恶性克隆可维持多个致癌病变，随着疾病进展累积遗传损伤（6，7）。目前的骨髓瘤治疗可以延长生存期，但不能治愈（8，9）。因此，需要靶向所有骨髓瘤亚型共有的分子途径的新的治疗策略。在这里，我们显示，使用功能丧失，RNA干扰为基础的遗传筛选，IRF 4抑制是有毒的骨髓瘤细胞系，无论转化致癌机制。基因表达谱分析和全基因组染色质免疫沉淀分析揭示了IRF 4靶基因的广泛网络，并将MYC鉴定为活化B细胞和骨髓瘤中IRF 4的直接靶点。出乎意料的是，IRF 4本身是MYC反式激活的直接靶点，在骨髓瘤细胞中产生了一个自动调节回路。虽然IRF 4在大多数骨髓瘤中没有遗传改变，但它们仍然对融合正常浆细胞和活化B细胞的基因表达程序的异常IRF 4调节网络上瘾。
The transcription factor IRF4 ( interferon regulatory factor 4) is required during an immune response for lymphocyte activation and the generation of immunoglobulin- secreting plasma cells(1-3). Multiple myeloma, a malignancy of plasma cells, has a complex molecular aetiology with several subgroups defined by gene expression profiling and recurrent chromosomal translocations(4,5). Moreover, the malignant clone can sustain multiple oncogenic lesions, accumulating genetic damage as the disease progresses(6,7). Current therapies for myeloma can extend survival but are not curative(8,9). Hence, new therapeutic strategies are needed that target molecular pathways shared by all subtypes of myeloma. Here we show, using a loss- of- function, RNA- interference- based genetic screen, that IRF4 inhibition is toxic to myeloma cell lines, regardless of transforming oncogenic mechanism. Gene expression profiling and genome- wide chromatin immunoprecipitation analysis uncovered an extensive network of IRF4 target genes and identified MYC as a direct target of IRF4 in activated B cells and myeloma. Unexpectedly, IRF4 was itself a direct target of MYC transactivation, generating an autoregulatory circuit in myeloma cells. Although IRF4 is not genetically altered in most myelomas, they are nonetheless addicted to an aberrant IRF4 regulatory network that fuses the gene expression programmes of normal plasma cells and activated B cells.