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IL-4 producing follicular helper T cells (T<jats:sub>FH<\/jats:sub>) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK\/STAT signaling. We identified <jats:italic>STAT6<\/jats:italic> mutations (<jats:italic>STAT6<\/jats:italic><jats:sup>MUT<\/jats:sup>) in 13% of FL (<jats:italic>N<\/jats:italic>\u2009=\u200933\/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4\/STAT6 target genes in <jats:italic>STAT6<\/jats:italic><jats:sup>MUT<\/jats:sup> FL, including <jats:italic>CCL17<\/jats:italic>, <jats:italic>CCL22<\/jats:italic>, and <jats:italic>FCER2<\/jats:italic> (CD23). Functionally, <jats:italic>STAT6<\/jats:italic><jats:sup>MUT<\/jats:sup> was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6<jats:sup>MUT<\/jats:sup> enhanced IL-4 induced <jats:italic>FCER2<\/jats:italic>\/CD23, <jats:italic>CCL17<\/jats:italic> and <jats:italic>CCL22<\/jats:italic> 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 <jats:italic>STAT6<\/jats:italic><jats:sup>MUT<\/jats:sup> lymphoma cells and in <jats:italic>STAT6<\/jats:italic><jats:sup>MUT<\/jats:sup> primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6<jats:sup>MUT<\/jats:sup> but not STAT6<jats:sup>WT<\/jats:sup> to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6<jats:sup>MUT<\/jats:sup> at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6<jats:sup>MUT<\/jats:sup> gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in <jats:italic>STAT6<\/jats:italic><jats:sup>MUT<\/jats:sup> FL.<\/jats:p>","DOI":"10.1038\/s41375-022-01641-x","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T18:09:12Z","timestamp":1658167752000},"page":"2281-2292","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["PARP14 is a novel target in STAT6 mutant follicular lymphoma"],"prefix":"10.1038","volume":"36","author":[{"given":"Michael","family":"Mentz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8794-7322","authenticated-orcid":false,"given":"William","family":"Keay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2257-6281","authenticated-orcid":false,"given":"Carolin 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(DKH, German Cancer Aid), Project-ID 110659\/70112997 (OW). OW is supported by an Else-Kr\u00f6ner Excellence Fellowship from the Else-Kr\u00f6ner-Fresenius Stiftung (Project-ID 2021_EKES.13). LA is supported by the Else Kr\u00f6ner-Fresenius Clinician Scientist Program: Cancer immunotherapy, and the Munich Clinician Scientist Program (MCSP). LA and JAH are supported by the German Consortium for Translational Cancer Research (DKTK) School of Oncology. MS, Amgen, Speakers Bureau. The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}