Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
Dr Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School, Frankfurt, Germany.
Leukemia. 2018 Jan;32(1):92-101. doi: 10.1038/leu.2017.203. Epub 2017 Jun 29.
Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30 lymphomas, namely cHL (21/30) and primary mediastinal B-cell lymphoma (8/9), but also CD30 diffuse large B-cell lymphoma (15/20) frequently express BATF3 protein. Mass spectrometry and co-immunoprecipitation established interactions of BATF3 with JUN and JUNB in cHL and ALCL lines. BATF3 knockdown using short hairpin RNAs was toxic for cHL and ALCL lines, reducing their proliferation and survival. We identified MYC as a critical BATF3 target and confirmed binding of BATF3 to the MYC promoter. JAK/STAT signaling regulated BATF3 expression, as chemical JAK2 inhibition reduced and interleukin 13 stimulation induced BATF3 expression in cHL lines. Chromatin immunoprecipitation substantiated a direct regulation of BATF3 by STAT proteins in cHL and ALCL lines. In conclusion, we identified STAT-mediated BATF3 expression that is essential for lymphoma cell survival and promoted MYC activity in cHL and ALCL, hence we recognized a new oncogenic axis in these lymphomas.
经典霍奇金淋巴瘤（cHL）和间变大细胞淋巴瘤（ALCL）表现出高表达激活蛋白-1（AP-1）转录因子，这些转录因子调节各种生理过程，但也促进淋巴瘤的发生。AP-1 因子碱性亮氨酸拉链转录因子，ATF 样 3（BATF3），在 cHL 和 ALCL 中高度转录；然而，其在淋巴瘤发生中的功能重要性尚不清楚。在这里，我们发现典型的 CD30 淋巴瘤，即 cHL（21/30）和原发性纵隔 B 细胞淋巴瘤（8/9），但也包括 CD30 弥漫性大 B 细胞淋巴瘤（15/20），频繁表达 BATF3 蛋白。质谱和共免疫沉淀确定了 BATF3 在 cHL 和 ALCL 细胞系中与 JUN 和 JUNB 的相互作用。使用短发夹 RNA 敲低 BATF3 对 cHL 和 ALCL 细胞系有毒，降低其增殖和存活。我们确定 MYC 是 BATF3 的一个关键靶点，并证实了 BATF3 与 MYC 启动子的结合。JAK/STAT 信号转导调节 BATF3 的表达，因为化学 JAK2 抑制减少和白细胞介素 13 刺激诱导 cHL 细胞系中 BATF3 的表达。染色质免疫沉淀证实了 STAT 蛋白在 cHL 和 ALCL 细胞系中对 BATF3 的直接调节。总之，我们确定了 STAT 介导的 BATF3 表达，这对于淋巴瘤细胞的存活是必不可少的，并促进了 cHL 和 ALCL 中的 MYC 活性，因此我们在这些淋巴瘤中识别出一个新的致癌轴。
