Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma
Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma
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DOI：
10.1182/blood-2014-08-594507
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发表时间：
2015-01-01
期刊：
影响因子：
20.3
通讯作者：
Lenz, Georg
中科院分区：
文献类型：
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作者：
Weilemann, Andre;Grau, Michael;Lenz, Georg
间变性大细胞淋巴瘤（ALCL）是一种不同的t细胞淋巴瘤，根据涉及ALKgene易位的存在可分为2种亚型（ALK和ALK(-) ALCL）。干扰素调节因子4 （IRF4）在ALK和ALK- alcl中均有高表达。然而，IRF4在这些淋巴瘤发病机制中的作用尚不清楚。在这里，我们发现这两种亚型的ALCL都依赖于IRF4信号，因为通过RNA干扰敲低IRF4对ALCL细胞系和体内ALCL异种移植小鼠模型具有毒性。IRF4敲低后的基因表达谱显示了多种已知MYC靶基因的显著下调。此外，我们的分析显示MYC是IRF4的主要靶点，确定了ALCL中MYC表达的一种新的调控机制及其靶基因网络。MYC本身对于ALCL的生存至关重要，因为MYC的敲低和MYC信号的药理抑制对ALCL细胞系都是有毒的。总的来说，我们的研究结果表明，alcl依赖于IRF4和MYC信号，MYC可能是未来治疗的一个有希望的靶点。
Anaplastic large cell lymphoma (ALCL) is a distinct entity of T-cell lymphoma that can be divided into 2 subtypes based on the presence of translocations involving the ALKgene(ALK and ALK(-) ALCL). The interferon regulatory factor 4 (IRF4) is known to be highly expressed in both ALK and ALK- ALCLs. However, the role of IRF4 in the pathogenesis of these lymphomas remains unclear. Here we show that ALCLs of both subtypes are addicted to I RF4 signaling, as knockdown of IRF4 by RNA interference was toxic to ALCL cell lines in vitro and in ALCL xenograft mouse models in vivo. Gene expression profiling after IRF4 knockdown demonstrated a significant downregulation of a variety of known MYC target genes. Furthermore, our analyses revealed that MYC is a primary target of IRF4, identifying a novel regulatory mechanism of MYC expression and its target gene network in ALCL. MYC, itself, is essential for ALCL survival, as both knockdown of MYC and pharmacologic inhibition of MYC signaling were toxic to ALCL cell lines. Collectively, our results demonstrate that ALCLs are dependent on IRF4 and MYC signaling and that MYC may represent a promising target for future therapies.