PARP14是STAT6突变滤泡性淋巴瘤的新靶点,Leukemia

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PARP14是STAT6突变滤泡性淋巴瘤的新靶点
Leukemia ( IF 12.8 ) Pub Date : 2022-07-18 , DOI: 10.1038/s41375-022-01641-x
Michael Mentz _{1,

2} , William Keay ₁ , Carolin Dorothea Strobl ₁ , Martina Antoniolli ₁ , Louisa Adolph ₁ , Michael Heide ₁ , Axel Lechner ₃ , Sarah Haebe _{1,

4} , Elisa Osterode ₁ , Robert Kridel ₅ , Christoph Ziegenhain ₆ , Lucas Esteban Wange ₆ , Johannes Adrian Hildebrand ₁ , Tanaya Shree ₄ , Elisabeth Silkenstedt ₁ , Annette M Staiger _{7,

8} , German Ott ₇ , Heike Horn _{7,

8} , Monika Szczepanowski ₉ , Julia Richter ₉ , Ronald Levy ₄ , Andreas Rosenwald ₁₀ , Wolfgang Enard ₄ , Ursula Zimber-Strobl ₂ , Michael von Bergwelt-Baildon _{1,

11,

12} , Wolfgang Hiddemann _{1,

11,

12} , Wolfram Klapper ₉ , Marc Schmidt-Supprian _{11,

12,

13} , Martina Rudelius ₁₄ , Deepak Bararia ₁ , Verena Passerini ₁ , Oliver Weigert _{1,

11,

12}

Affiliation

Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Ludwig-Maximilians-University (LMU) Hospital, Munich, Germany.
Research Unit Gene Vectors, Helmholtz- Center Munich, German Research Center for Environmental Health, Munich, Germany.
Department of Otolaryngology, Ludwig-Maximilians-University (LMU) Hospital, Munich, Germany.
Division of Oncology, Department of Medicine, School of Medicine, Stanford, CA, USA.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Anthropology and Human Genomics, Faculty of Biology, Ludwig-Maximilians-University, Munich, Germany.
Department of Clinical Pathology, Robert Bosch Hospital, Stuttgart, Germany.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany.
Institute of Pathology, Hematopathology Section, University of Schleswig-Holstein, Kiel, Germany.
Institute of Pathology, University of Würzburg and Comprehensive Cancer Centre Mainfranken, Würzburg, Germany.
German Cancer Consortium (DKTK), Munich, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Institute of Experimental Hematology, School of Medicine, Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany.
Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany.

滤泡性淋巴瘤（FL）的可变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 (T _FH ) 是 FL TME 的关键组成部分。FL 细胞上 IL-4 与 IL-4R 的结合激活 JAK/STAT 信号传导。我们在 13% 的 FL ( N = 33/258) 中发现了STAT6突变 ( STAT6 ^MUT ) ，所有突变都聚集在 DNA 结合域内。基因表达数据和免疫组织化学显示STAT6 ^MUT FL中 IL-4/STAT6 靶基因上调，包括CCL17、CCL22和FCER2 (CD23)。在功能上，STAT6 ^MUT通过在 B 前 CFU 测定中连续重新接种表型而获得功能。STAT6 ^MUT的表达增强了 IL-4 诱导的FCER2 /CD23、CCL17和CCL22表达，并与 pSTAT6 的核积累相关。RNA 测序鉴定出 PARP14（一种转录开关和 STAT6 的共激活因子）是 IL-4 刺激的STAT6 ^MUT淋巴瘤细胞和STAT6 ^MUT原代 FL 细胞中差异上调最多的基因之一。定量染色质免疫沉淀 (qChIP) 证明 STAT6 ^MUT（而非 STAT6 ^WT）与 PARP14 启动子结合。报告基因检测显示，IL-4 诱导的PARP14 启动子处的STAT6 ^{MUT反式激活活性增加，表明存在自我强化的调节回路。}PARP14 的敲低或 PARP 抑制消除了 STAT6 ^MUT功能获得表型。因此，我们的结果将 PARP14 确定为STAT6 ^MUT FL的新治疗靶点。

"点击查看英文标题和摘要"

PARP14 is a novel target in STAT6 mutant follicular lymphoma

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 (T_FH) 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 (STAT6^MUT) 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 STAT6^MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6^MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6^MUT 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 STAT6^MUT lymphoma cells and in STAT6^MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6^MUT but not STAT6^WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6^MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6^MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6^MUT FL.

更新日期：2022-07-19

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