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.

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。