{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T03:13:12Z","timestamp":1740107592213,"version":"3.37.3"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T00:00:00Z","timestamp":1654300800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T00:00:00Z","timestamp":1654300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100008375","name":"University of Basel","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008375","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Virchows Arch"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Approximately 15% of follicular lymphomas (FL) lack overexpression of BCL2 and the underlying translocation t(14;18). These cases can be diagnostically challenging, especially regarding follicular hyperplasia (FH). In a subset of FL, mutations in genes encoding for epigenetic modifiers, such as the histone-lysine N-methyltransferase <jats:italic>EZH2<\/jats:italic> (enhancer of zeste homolog 2), were found, which might be used diagnostically. These molecular alterations can lead to an increased tri-methylation of histone H3 at position lysine 27 (H3K27m3) that, in turn, can be visualized immunohistochemically. The aim of this study was to analyze the expression of H3K27m3 in FL, primary cutaneous follicle center lymphomas (PCFCL), and pediatric-type FL (PTFL) in order to investigate its value in the differential diagnosis to FH and other B cell lymphomas and to correlate it to BCL2 expression and the presence of t(14;18). Additionally, the mutational profile of selected cases was considered to address H3K27m3\u2019s potential use as a surrogate parameter for mutations in genes encoding for epigenetic modifiers. Eighty-nine percent of FL and 100% of PCFCL cases overexpressed H3K27m3, independently of BCL2,\u00a0EZH2, and the presence of mutations. In contrast, 95% of FH and 100% of PTFL cases lacked H3K27m3 overexpression. Other B cell lymphomas considered for differential diagnosis also showed overexpression of H3K27m3 in the majority of cases. In summary, overexpression of H3K27m3 can serve as a new, BCL2\u00a0independent marker in the differential diagnosis of FL and PCFCL, but not PTFL, to FH, while being not of help in the differential diagnosis of FL to other B cell lymphomas.<\/jats:p>","DOI":"10.1007\/s00428-022-03347-y","type":"journal-article","created":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T13:02:43Z","timestamp":1654347763000},"page":"489-497","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["H3K27m3 overexpression as a new, BCL2 independent diagnostic tool in follicular and cutaneous follicle center lymphomas"],"prefix":"10.1007","volume":"481","author":[{"given":"Magdalena M.","family":"Brune","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Visar","family":"Vela","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivana","family":"Bratic Hench","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Dertinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Borgmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Dirnhofer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1100-3819","authenticated-orcid":false,"given":"Alexandar","family":"Tzankov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,6,4]]},"reference":[{"key":"3347_CR1","doi-asserted-by":"publisher","first-page":"3424","DOI":"10.1172\/JCI63186","volume":"122","author":"R Kridel","year":"2012","unstructured":"Kridel R, Sehn LH, Gascoyne RD (2012) Pathogenesis of follicular lymphoma. J Clin Invest 122:3424\u20133431. https:\/\/doi.org\/10.1172\/JCI63186","journal-title":"J Clin Invest"},{"key":"3347_CR2","unstructured":"Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues, Revisied 4th. International Agency for Research on Cancer, Lyon"},{"key":"3347_CR3","doi-asserted-by":"publisher","first-page":"5652","DOI":"10.1182\/bloodadvances.2020002944","volume":"4","author":"D Nann","year":"2020","unstructured":"Nann D, Ramis-Zaldivar JE, M\u00fcller I et al (2020) Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease. Blood Adv 4:5652\u20135665. https:\/\/doi.org\/10.1182\/bloodadvances.2020002944","journal-title":"Blood Adv"},{"key":"3347_CR4","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/ng.2856","volume":"46","author":"J Okosun","year":"2014","unstructured":"Okosun J, B\u00f6d\u00f6r C, Wang J et al (2014) Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 46:176\u2013181. https:\/\/doi.org\/10.1038\/ng.2856","journal-title":"Nat Genet"},{"key":"3347_CR5","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/nature09784","volume":"469","author":"R Margueron","year":"2011","unstructured":"Margueron R, Reinberg D (2011) The polycomb complex PRC2 and its mark in life. Nature 469:343\u2013349. https:\/\/doi.org\/10.1038\/nature09784","journal-title":"Nature"},{"key":"3347_CR6","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1007\/s00018-017-2596-8","volume":"75","author":"M-R Pan","year":"2018","unstructured":"Pan M-R, Hsu M-C, Chen L-T, Hung W-C (2018) Orchestration of H3K27 methylation: mechanisms and therapeutic implication. Cell Mol Life Sci 75:209\u2013223. https:\/\/doi.org\/10.1007\/s00018-017-2596-8","journal-title":"Cell Mol Life Sci"},{"key":"3347_CR7","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1038\/s41467-017-01029-x","volume":"8","author":"W B\u00e9guelin","year":"2017","unstructured":"B\u00e9guelin W, Rivas MA, Calvo Fern\u00e1ndez MT et al (2017) EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop. Nat Commun 8:877. https:\/\/doi.org\/10.1038\/s41467-017-01029-x","journal-title":"Nat Commun"},{"key":"3347_CR8","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/ng.518","volume":"42","author":"RD Morin","year":"2010","unstructured":"Morin RD, Johnson NA, Severson TM et al (2010) Somatic mutation of EZH2 (Y641) in follicular and diffuse large B-cell lymphomas of germinal center origin. Nat Genet 42:181\u2013185. https:\/\/doi.org\/10.1038\/ng.518","journal-title":"Nat Genet"},{"key":"3347_CR9","doi-asserted-by":"publisher","first-page":"e555","DOI":"10.1038\/bcj.2017.32","volume":"7","author":"S Huet","year":"2017","unstructured":"Huet S, Xerri L, Tesson B et al (2017) EZH2 alterations in follicular lymphoma: biological and clinical correlations. Blood Cancer J 7:e555. https:\/\/doi.org\/10.1038\/bcj.2017.32","journal-title":"Blood Cancer J"},{"key":"3347_CR10","doi-asserted-by":"publisher","first-page":"20980","DOI":"10.1073\/pnas.1012525107","volume":"107","author":"CJ Sneeringer","year":"2010","unstructured":"Sneeringer CJ, Scott MP, Kuntz KW et al (2010) Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci 107:20980\u201320985. https:\/\/doi.org\/10.1073\/pnas.1012525107","journal-title":"Proc Natl Acad Sci"},{"key":"3347_CR11","doi-asserted-by":"publisher","first-page":"3465","DOI":"10.1182\/blood.V114.22.3465.3465","volume":"114","author":"I Velichutina","year":"2009","unstructured":"Velichutina I, Shaknovich R, Geng H et al (2009) EZH2 mediates DNA methylation-independent epigenetic silencing of a germinal center specific transcriptional program that contributes to cellular proliferation and lymphomagenesis. Blood 114:3465\u20133465. https:\/\/doi.org\/10.1182\/blood.V114.22.3465.3465","journal-title":"Blood"},{"key":"3347_CR12","doi-asserted-by":"publisher","first-page":"2989","DOI":"10.1073\/pnas.1116418109","volume":"109","author":"MT McCabe","year":"2012","unstructured":"McCabe MT, Graves AP, Ganji G et al (2012) Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci 109:2989\u20132994. https:\/\/doi.org\/10.1073\/pnas.1116418109","journal-title":"Proc Natl Acad Sci"},{"key":"3347_CR13","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/nature11606","volume":"492","author":"MT McCabe","year":"2012","unstructured":"McCabe MT, Ott HM, Ganji G et al (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492:108\u2013112. https:\/\/doi.org\/10.1038\/nature11606","journal-title":"Nature"},{"key":"3347_CR14","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1182\/blood-2019-128096","volume":"134","author":"F Morschhauser","year":"2019","unstructured":"Morschhauser F, Tilly H, Chaidos A et al (2019) Phase 2 multicenter study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory follicular lymphoma. Blood 134:123\u2013123. https:\/\/doi.org\/10.1182\/blood-2019-128096","journal-title":"Blood"},{"key":"3347_CR15","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1016\/S1470-2045(20)30441-1","volume":"21","author":"F Morschhauser","year":"2020","unstructured":"Morschhauser F, Tilly H, Chaidos A et al (2020) Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol 21:1433\u20131442. https:\/\/doi.org\/10.1016\/S1470-2045(20)30441-1","journal-title":"Lancet Oncol"},{"key":"3347_CR16","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/S0002-9440(10)64583-X","volume":"157","author":"FM Raaphorst","year":"2000","unstructured":"Raaphorst FM, van Kemenade FJ, Blokzijl T et al (2000) Coexpression of BMI-1 and EZH2 polycomb group genes in Reed-Sternberg cells of Hodgkin\u2019s disease. Am J Pathol 157:709\u2013715. https:\/\/doi.org\/10.1016\/S0002-9440(10)64583-X","journal-title":"Am J Pathol"},{"key":"3347_CR17","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/j.molonc.2012.06.002","volume":"6","author":"K Holm","year":"2012","unstructured":"Holm K, Grabau D, L\u00f6vgren K et al (2012) Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes. Mol Oncol 6:494\u2013506. https:\/\/doi.org\/10.1016\/j.molonc.2012.06.002","journal-title":"Mol Oncol"},{"key":"3347_CR18","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.3390\/biomedicines9121842","volume":"9","author":"FL Sch\u00fcmann","year":"2021","unstructured":"Sch\u00fcmann FL, Gro\u00df E, Bauer M et al (2021) Divergent effects of EZH1 and EZH2 protein expression on the prognosis of patients with T-cell lymphomas. Biomedicines 9:1842. https:\/\/doi.org\/10.3390\/biomedicines9121842","journal-title":"Biomedicines"},{"key":"3347_CR19","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/s13045-017-0438-7","volume":"10","author":"D Juskevicius","year":"2017","unstructured":"Juskevicius D, Jucker D, Klingbiel D et al (2017) Mutations of CREBBP and SOCS1 are independent prognostic factors in diffuse large B cell lymphoma: mutational analysis of the SAKK 38\/07 prospective clinical trial cohort. J Hematol OncolJ Hematol Oncol 10:70. https:\/\/doi.org\/10.1186\/s13045-017-0438-7","journal-title":"J Hematol OncolJ Hematol Oncol"},{"key":"3347_CR20","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1111\/bjh.16414","volume":"189","author":"T Menter","year":"2020","unstructured":"Menter T, Tzankov A, Zucca E et al (2020) Prognostic implications of the microenvironment for follicular lymphoma under immunomodulation therapy. Br J Haematol 189:707\u2013717. https:\/\/doi.org\/10.1111\/bjh.16414","journal-title":"Br J Haematol"},{"key":"3347_CR21","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1136\/jcp.2006.038661","volume":"60","author":"A Tzankov","year":"2007","unstructured":"Tzankov A, Heiss S, Ebner S et al (2007) Angiogenesis in nodal B cell lymphomas: a high throughput study. J Clin Pathol 60:476\u2013482. https:\/\/doi.org\/10.1136\/jcp.2006.038661","journal-title":"J Clin Pathol"},{"key":"3347_CR22","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/s13045-015-0168-7","volume":"8","author":"A Tzankov","year":"2015","unstructured":"Tzankov A, Leu N, Muenst S et al (2015) Multiparameter analysis of homogeneously R-CHOP-treated diffuse large B cell lymphomas identifies CD5 and FOXP1 as relevant prognostic biomarkers: report of the prospective SAKK 38\/07 study. J Hematol OncolJ Hematol Oncol 8:70. https:\/\/doi.org\/10.1186\/s13045-015-0168-7","journal-title":"J Hematol OncolJ Hematol Oncol"},{"key":"3347_CR23","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1182\/blood-2017-03-776278","volume":"130","author":"J Schmidt","year":"2017","unstructured":"Schmidt J, Ramis-Zaldivar JE, Nadeu F et al (2017) Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation. Blood 130:323\u2013327. https:\/\/doi.org\/10.1182\/blood-2017-03-776278","journal-title":"Blood"},{"key":"3347_CR24","doi-asserted-by":"publisher","first-page":"2568","DOI":"10.1080\/10428194.2020.1786560","volume":"61","author":"V Pillonel","year":"2020","unstructured":"Pillonel V, Juskevicius D, Bihl M et al (2020) Routine next generation sequencing of lymphoid malignancies: clinical utility and challenges from a 3-year practical experience. Leuk Lymphoma 61:2568\u20132583. https:\/\/doi.org\/10.1080\/10428194.2020.1786560","journal-title":"Leuk Lymphoma"},{"key":"3347_CR25","doi-asserted-by":"publisher","first-page":"97","DOI":"10.46883\/2022.25920946","volume":"36","author":"KE Cahill","year":"2022","unstructured":"Cahill KE, Smith SM (2022) Follicular lymphoma: a focus on current and emerging therapies. Oncol Williston Park N 36:97\u2013106. https:\/\/doi.org\/10.46883\/2022.25920946","journal-title":"Oncol Williston Park N"},{"key":"3347_CR26","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1158\/1535-7163.MCT-21-0216","volume":"21","author":"SEJ Preston","year":"2022","unstructured":"Preston SEJ, Emond A, Pettersson F et al (2022) Acquired resistance to EZH2 inhibitor GSK343 promotes the differentiation of human DLBCL cell lines toward an ABC-like phenotype. Mol Cancer Ther 21:511\u2013521. https:\/\/doi.org\/10.1158\/1535-7163.MCT-21-0216","journal-title":"Mol Cancer Ther"},{"key":"3347_CR27","doi-asserted-by":"publisher","first-page":"16712","DOI":"10.18632\/oncotarget.3154","volume":"6","author":"S Dubois","year":"2015","unstructured":"Dubois S, Mareschal S, Picquenot J-M et al (2015) Immunohistochemical and genomic profiles of diffuse large B-cell lymphomas: implications for targeted EZH2 inhibitor therapy. Oncotarget 6:16712\u201316724. https:\/\/doi.org\/10.18632\/oncotarget.3154","journal-title":"Oncotarget"},{"key":"3347_CR28","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1182\/blood-2015-12-682591","volume":"128","author":"A Louissaint","year":"2016","unstructured":"Louissaint A, Schafernak KT, Geyer JT et al (2016) Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations. Blood 128:1093\u20131100. https:\/\/doi.org\/10.1182\/blood-2015-12-682591","journal-title":"Blood"},{"key":"3347_CR29","doi-asserted-by":"publisher","first-page":"20130514","DOI":"10.1098\/rstb.2013.0514","volume":"369","author":"E Shen","year":"2014","unstructured":"Shen E, Shulha H, Weng Z, Akbarian S (2014) Regulation of histone H3K4 methylation in brain development and disease. Philos Trans R Soc Lond B Biol Sci 369:20130514. https:\/\/doi.org\/10.1098\/rstb.2013.0514","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"3347_CR30","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1182\/blood.2021012386","volume":"139","author":"F Bonfiglio","year":"2022","unstructured":"Bonfiglio F, Bruscaggin A, Guidetti F et al (2022) Genetic and phenotypic attributes of splenic marginal zone lymphoma. Blood 139:732\u2013747. https:\/\/doi.org\/10.1182\/blood.2021012386","journal-title":"Blood"},{"key":"3347_CR31","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1016\/S1470-2045(15)00169-2","volume":"16","author":"A Pastore","year":"2015","unstructured":"Pastore A, Jurinovic V, Kridel R et al (2015) Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol 16:1111\u20131122. https:\/\/doi.org\/10.1016\/S1470-2045(15)00169-2","journal-title":"Lancet Oncol"},{"key":"3347_CR32","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1126\/science.1149042","volume":"318","author":"MG Lee","year":"2007","unstructured":"Lee MG, Villa R, Trojer P et al (2007) Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318:447\u2013450. https:\/\/doi.org\/10.1126\/science.1149042","journal-title":"Science"},{"key":"3347_CR33","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.3324\/haematol.2019.222935","volume":"105","author":"S Xie","year":"2020","unstructured":"Xie S, Wei F, Sun Y-M et al (2020) EZH2 inhibitors abrogate upregulation of trimethylation of H3K27 by CDK9 inhibitors and potentiate its activity against diffuse large B-cell lymphoma. Haematologica 105:1021\u20131031. https:\/\/doi.org\/10.3324\/haematol.2019.222935","journal-title":"Haematologica"},{"key":"3347_CR34","doi-asserted-by":"publisher","first-page":"e91330","DOI":"10.1371\/journal.pone.0091330","volume":"9","author":"A Hayashi","year":"2014","unstructured":"Hayashi A, Yamauchi N, Shibahara J et al (2014) Concurrent activation of acetylation and tri-methylation of H3K27 in a subset of hepatocellular carcinoma with aggressive behavior. PLoS ONE 9:e91330. https:\/\/doi.org\/10.1371\/journal.pone.0091330","journal-title":"PLoS ONE"}],"container-title":["Virchows Archiv"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-022-03347-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00428-022-03347-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-022-03347-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T17:07:33Z","timestamp":1663607253000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00428-022-03347-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,4]]},"references-count":34,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["3347"],"URL":"https:\/\/doi.org\/10.1007\/s00428-022-03347-y","relation":{},"ISSN":["0945-6317","1432-2307"],"issn-type":[{"type":"print","value":"0945-6317"},{"type":"electronic","value":"1432-2307"}],"subject":[],"published":{"date-parts":[[2022,6,4]]},"assertion":[{"value":"28 February 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 May 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 May 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 June 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study design was approved by the Ethics Committee of the University Hospital Basel (EKNZ-2014\u2013252). The procedures used in this study adhere to the tenets of the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}