PARP14 is a novel target in STAT6 mutant follicular lymphoma.
PARP14 is a novel target in STAT6 mutant follicular lymphoma.
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DOI：
10.1038/s41375-022-01641-x
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发表时间：
2022-09
期刊：
影响因子：
11.4
通讯作者：
Weigert, Oliver
中科院分区：
文献类型：
--
作者：
Mentz, Michael;Keay, William;Strobl, Carolin Dorothea;Antoniolli, Martina;Adolph, Louisa;Heide, Michael;Lechner, Axel;Haebe, Sarah;Osterode, Elisa;Kridel, Robert;Ziegenhain, Christoph;Wange, Lucas Esteban;Hildebrand, Johannes Adrian;Shree, Tanaya;Silkenstedt, Elisabeth;Staiger, Annette M.;Ott, German;Horn, Heike;Szczepanowski, Monika;Richter, Julia;Levy, Ronald;Rosenwald, Andreas;Enard, Wolfgang;Zimber-Strobl, Ursula;Von Bergwelt-Baildon, Michael;Hiddemann, Wolfgang;Klapper, Wolfram;Schmidt-Supprian, Marc;Rudelius, Martina;Bararia, Deepak;Passerini, Verena;Weigert, Oliver
滤泡性淋巴瘤(FL)的不同临床病程是由肿瘤细胞的分子异质性和肿瘤微环境(TME)内复杂的相互作用决定的。产生IL-4的滤泡辅助T细胞(TFH)是FL TME的重要组成部分。IL-4与FL细胞上的IL-4R结合可激活JAK/STAT信号。我们在13%的FL(N = 33/2 5 8)中发现了STAT6突变(STAT6MUT)，这些突变都聚集在DNA结合区内。基因表达数据和免疫组织化学结果显示，在STAT6MUT FL中，IL-4/STAT6靶基因表达上调，包括CCL17、CCL22和FCER2(CD23)。在功能上，STAT6MUT在Pre-B CFU分析中是通过连续重复表型而获得的。STAT6MUT的表达增强了IL-4诱导的FCER2/CD23、CCL17和CCL22的表达，并与pSTAT6的核积聚有关。RNA测序发现，在IL-4刺激的STAT6MUT淋巴瘤细胞和STAT6MUT原代FL细胞中，转录开关和STAT6的共激活因子PARP14是差异表达最高的基因之一。染色质定量免疫沉淀(QChIP)显示STAT6MUT与PARP14启动子结合，但不能与STAT6WT结合。报告分析显示，IL-4诱导的STAT6MUT在PARP14启动子上的反式激活活性增加，这表明了一种自我增强的调节电路。PARP14基因敲除或PARP抑制使STAT6MUT功能增益表型消失。因此，我们的结果确定PARP14是STAT6MUT FL的一个新的治疗靶点。
The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.
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影响因子：
30.8
作者：
Okosun, Jessica;Boedoer, Csaba;Wang, Jun;Araf, Shamzah;Yang, Cheng-Yuan;Pan, Chenyi;Boller, Soeren;Cittaro, Davide;Bozek, Monika;Iqbal, Sameena;Matthews, Janet;Wrench, David;Marzec, Jacek;Tawana, Kiran;Popov, Nikolay;O'Riain, Ciaran;O'Shea, Derville;Carlotti, Emanuela;Davies, Andrew;Lawrie, Charles H.;Matolcsy, Andras;Calaminici, Maria;Norton, Andrew;Byers, Richard J.;Mein, Charles;Stupka, Elia;Lister, T. Andrew;Lenz, Georg;Montoto, Silvia;Gribben, John G.;Fan, Yuhong;Grosschedl, Rudolf;Chelala, Claude;Fitzgibbon, Jude
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作者：
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