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Here, we report RNA-seq based gene expression data on normal human lymph node derived B lymphocytes (NBC; <jats:italic>N<\/jats:italic>\u2009=\u20096), and primary human FL WT (<jats:italic>N<\/jats:italic>\u2009=\u200911) or mutant (<jats:italic>N<\/jats:italic>\u2009=\u20094) for <jats:italic>STAT6<\/jats:italic> before and after ex vivo stimulation with IL4. We found that STAT6 mutants result in broad based augmentation of IL4-induced gene expression. Unexpectedly, in FL with WT <jats:italic>STAT6<\/jats:italic> we measured reduced baseline and IL4-induced gene expression levels when compared with NBC lymphocytes or FL with <jats:italic>STAT6<\/jats:italic> mutations. We tracked the attenuated IL4\/JAK\/STAT6 response to co-existing <jats:italic>CREBBP<\/jats:italic> mutations and experimentally verified that intact <jats:italic>CREBBP<\/jats:italic> is required for the induction of many IL4-induced genes. One of the IL4-induced genes here identified is <jats:italic>RRAGD<\/jats:italic>, a small G-protein involved in lysosomal mTOR activation. We show that IL4 treatment induced RRAGD expression, that RRAGD is required for mTOR activation in lymphoma cells and that IL4-enhanced BCR signaling induced mTOR activation. The IL4 and BCR-induced mTOR activation was reduced by <jats:italic>CREBBP<\/jats:italic> mutants and augmented by mutant STAT6, establishing a link between STAT6 mutations and mTOR regulated pro-growth pathways in lymphoma.<\/jats:p>","DOI":"10.1038\/s41375-025-02525-6","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T13:09:34Z","timestamp":1738760974000},"page":"899-908","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["STAT6 mutations compensate for CREBBP mutations and hyperactivate IL4\/STAT6\/RRAGD\/mTOR signaling in follicular lymphoma"],"prefix":"10.1038","volume":"39","author":[{"given":"Qiangqiang","family":"Shao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7843-738X","authenticated-orcid":false,"given":"Karan","family":"Bedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1395-487X","authenticated-orcid":false,"given":"Isabella A.","family":"Malek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerby","family":"Shedden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7734-4387","authenticated-orcid":false,"given":"Sami N.","family":"Malek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,5]]},"reference":[{"key":"2525_CR1","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1182\/blood-2005-06-2508","volume":"107","author":"LM Morton","year":"2006","unstructured":"Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. 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