Marialetizia Motta, Sabina Barresi, Simone Pizzi, Delfina Bifano, Jennifer Lopez Marti, Marta Garrido-Pontnou, Elisabetta Flex, Alessandro Bruselles, Isabella Giovannoni, Giovannina Rotundo, Alessandra Fragale, Valentina Tirelli, Silvia Vallese, Andrea Ciolfi, Gianni Bisogno, Rita Alaggio, Marco Tartaglia
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{"title":"RAF1基因融合是婴儿纤维肉瘤样间质肿瘤中反复出现的驱动事件","authors":"Marialetizia Motta, Sabina Barresi, Simone Pizzi, Delfina Bifano, Jennifer Lopez Marti, Marta Garrido-Pontnou, Elisabetta Flex, Alessandro Bruselles, Isabella Giovannoni, Giovannina Rotundo, Alessandra Fragale, Valentina Tirelli, Silvia Vallese, Andrea Ciolfi, Gianni Bisogno, Rita Alaggio, Marco Tartaglia","doi":"10.1002/path.6272","DOIUrl":null,"url":null,"abstract":"<p>Infantile fibrosarcomas (IFS) and congenital mesoblastic nephroma (CMN) are rare myofibroblastic tumors of infancy and early childhood commonly harboring the <i>ETV6</i>::<i>NTRK3</i> gene fusion. IFS/CMN are considered as tumors with an ‘intermediate prognosis’ as they are locally aggressive, but rarely metastasize, and generally have a favorable outcome. A fraction of IFS/CMN-related neoplasms are negative for the <i>ETV6</i>::<i>NTRK3</i> gene rearrangement and are characterized by other chimeric proteins promoting MAPK signaling upregulation. In a large proportion of these tumors, which are classified as IFS-like mesenchymal neoplasms, the contributing molecular events remain to be identified. Here, we report three distinct rearrangements involving <i>RAF1</i> among eight <i>ETV6</i>::<i>NTRK3</i> gene fusion-negative tumors with an original histological diagnosis of IFS/CMN. The three fusion proteins retain the entire catalytic domain of the kinase. Two chimeric products, GOLGA4::RAF1 and LRRFIP2::RAF1, had previously been reported as driver events in different cancers, whereas the third, CLIP1::RAF1, represents a novel fusion protein. We demonstrate that CLIP1::RAF1 acts as a <i>bona fide</i> oncoprotein promoting cell proliferation and migration through constitutive upregulation of MAPK signaling. We show that the CLIP1::RAF1 hyperactive behavior does not require RAS activation and is mediated by constitutive 14-3-3 protein-independent dimerization of the chimeric protein. As previously reported for the ETV6::NTRK3 fusion protein, CLIP1::RAF1 similarly upregulates PI3K-AKT signaling. Our findings document that <i>RAF1</i> gene rearrangements represent a recurrent event in <i>ETV6</i>::<i>NTRK3</i>-negative IFS/CMN and provide a rationale for the use of inhibitors directed to suppress MAPK and PI3K-AKT signaling in these cancers. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 2","pages":"166-177"},"PeriodicalIF":5.6000,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma-like mesenchymal tumors\",\"authors\":\"Marialetizia Motta, Sabina Barresi, Simone Pizzi, Delfina Bifano, Jennifer Lopez Marti, Marta Garrido-Pontnou, Elisabetta Flex, Alessandro Bruselles, Isabella Giovannoni, Giovannina Rotundo, Alessandra Fragale, Valentina Tirelli, Silvia Vallese, Andrea Ciolfi, Gianni Bisogno, Rita Alaggio, Marco Tartaglia\",\"doi\":\"10.1002/path.6272\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Infantile fibrosarcomas (IFS) and congenital mesoblastic nephroma (CMN) are rare myofibroblastic tumors of infancy and early childhood commonly harboring the <i>ETV6</i>::<i>NTRK3</i> gene fusion. IFS/CMN are considered as tumors with an ‘intermediate prognosis’ as they are locally aggressive, but rarely metastasize, and generally have a favorable outcome. A fraction of IFS/CMN-related neoplasms are negative for the <i>ETV6</i>::<i>NTRK3</i> gene rearrangement and are characterized by other chimeric proteins promoting MAPK signaling upregulation. In a large proportion of these tumors, which are classified as IFS-like mesenchymal neoplasms, the contributing molecular events remain to be identified. Here, we report three distinct rearrangements involving <i>RAF1</i> among eight <i>ETV6</i>::<i>NTRK3</i> gene fusion-negative tumors with an original histological diagnosis of IFS/CMN. The three fusion proteins retain the entire catalytic domain of the kinase. Two chimeric products, GOLGA4::RAF1 and LRRFIP2::RAF1, had previously been reported as driver events in different cancers, whereas the third, CLIP1::RAF1, represents a novel fusion protein. We demonstrate that CLIP1::RAF1 acts as a <i>bona fide</i> oncoprotein promoting cell proliferation and migration through constitutive upregulation of MAPK signaling. We show that the CLIP1::RAF1 hyperactive behavior does not require RAS activation and is mediated by constitutive 14-3-3 protein-independent dimerization of the chimeric protein. As previously reported for the ETV6::NTRK3 fusion protein, CLIP1::RAF1 similarly upregulates PI3K-AKT signaling. Our findings document that <i>RAF1</i> gene rearrangements represent a recurrent event in <i>ETV6</i>::<i>NTRK3</i>-negative IFS/CMN and provide a rationale for the use of inhibitors directed to suppress MAPK and PI3K-AKT signaling in these cancers. © 2024 The Pathological Society of Great Britain and Ireland.</p>\",\"PeriodicalId\":232,\"journal\":{\"name\":\"The Journal of Pathology\",\"volume\":\"263 2\",\"pages\":\"166-177\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-04-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/path.6272\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/path.6272","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
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