{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:41:38Z","timestamp":1776339698254,"version":"3.51.2"},"reference-count":22,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2017,4,1]],"date-time":"2017-04-01T00:00:00Z","timestamp":1491004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["FKZ 0316043"],"award-info":[{"award-number":["FKZ 0316043"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>A high\u2010level expression of the <jats:italic>CRLF2<\/jats:italic> gene is frequent in precursor B\u2010cell acute lymphoblastic leukemia (pB\u2010ALL) and can be caused by different genetic aberrations. The presence of the most frequent alteration, the <jats:italic>P2RY8\/CRLF2<\/jats:italic> fusion, was shown to be associated with a high relapse incidence in children treated according to ALL\u2010Berlin\u2013Frankfurt\u2013M\u00fcnster (BFM) protocols, which is poorly understood. Moreover, the frequency of other alterations has not been systematically analyzed yet.<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedure<\/jats:title><jats:p><jats:italic>CRLF2<\/jats:italic> mRNA expression and potential genetic aberrations causing a <jats:italic>CRLF2<\/jats:italic> high expression were prospectively assessed in 1,105 patients treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)\u2013BFM ALL 2009 protocol. Additionally, we determined copy number alterations in selected B\u2010cell differentiation genes for all <jats:italic>CRLF2<\/jats:italic> high\u2010expressing pB\u2010ALL cases, as well as <jats:italic>JAK2<\/jats:italic> and <jats:italic>CRLF2<\/jats:italic> mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A <jats:italic>CRLF2<\/jats:italic> high expression was detected in 26\/178 (15%) T\u2010cell acute lymphoblastic leukemia (T\u2010ALL) cases, 21 of them (81%) had been stratified as high\u2010risk patients by treatment response. In pB\u2010ALL, a <jats:italic>CRLF2<\/jats:italic> high expression was determined in 91\/927 (10%) cases; the <jats:italic>P2RY8\/CRLF2<\/jats:italic> rearrangement in 44\/91 (48%) of them, supernumerary copies of <jats:italic>CRLF2<\/jats:italic> in 18\/91 (20%), and, notably, the IGH<jats:italic>\/CRLF2<\/jats:italic> translocation was detected in 16\/91 (18%). Remarkably, 7 of 16 (44%) patients with IGH<jats:italic>\/CRLF2<\/jats:italic> translocation had already relapsed. <jats:italic>P2RY8\/CRLF2<\/jats:italic>\u2010 and IGH<jats:italic>\/CRLF2<\/jats:italic>\u2010positive samples (70 and 94%, respectively) were characterized by a high frequency of additional deletions in B\u2010cell differentiation genes such as <jats:italic>IKZF1<\/jats:italic> or <jats:italic>PAX5<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data suggest that this high frequency of genetic aberrations in the context of a high <jats:italic>CRLF2<\/jats:italic> expression could contribute to the high risk of relapse in <jats:italic>P2RY8\/CRLF2<\/jats:italic>\u2010 and IGH<jats:italic>\/CRLF2<\/jats:italic>\u2010positive ALL.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.26539","type":"journal-article","created":{"date-parts":[[2017,4,4]],"date-time":"2017-04-04T07:54:23Z","timestamp":1491292463000},"source":"Crossref","is-referenced-by-count":32,"title":["Molecular characterization of acute lymphoblastic leukemia with high <i>CRLF2<\/i> gene expression in childhood"],"prefix":"10.1002","volume":"64","author":[{"given":"Juliane","family":"Schm\u00e4h","sequence":"first","affiliation":[{"name":"Department of Pediatrics University Medical Center Schleswig\u2010Holstein  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birthe","family":"Fedders","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Schleswig\u2010Holstein  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renate","family":"Panzer\u2010Gr\u00fcmayer","sequence":"additional","affiliation":[{"name":"Children's Cancer Research Institute, St. Anna Kinderkrebsforschung  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanna","family":"Fischer","sequence":"additional","affiliation":[{"name":"Children's Cancer Research Institute, St. Anna Kinderkrebsforschung  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Hannover Medical School  Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elif","family":"Dagdan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Hannover Medical School  Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Bens","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Christian\u2010Albrechts\u2010University Kiel &amp; University Medical Center Schleswig\u2010Holstein  Kiel Germany"},{"name":"Institute of Human Genetics University of Ulm  Ulm Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denis","family":"Schewe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Schleswig\u2010Holstein  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Moericke","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Schleswig\u2010Holstein  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Alten","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Schleswig\u2010Holstein  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirsten","family":"Bleckmann","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Schleswig\u2010Holstein  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reiner","family":"Siebert","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Christian\u2010Albrechts\u2010University Kiel &amp; University Medical Center Schleswig\u2010Holstein  Kiel Germany"},{"name":"Institute of Human Genetics University of Ulm  Ulm Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Schrappe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Schleswig\u2010Holstein  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Stanulla","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Hannover Medical School  Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gunnar","family":"Cario","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Schleswig\u2010Holstein  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-10-248146"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2008.5"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.469"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-03-208397"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2012.101"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-07-443218"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-11-256131"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22190"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-11-394221"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.10610"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-08-235408"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.10169"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.2353\/jmoldx.2006.050083"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1214\/aoms\/1177730491"},{"issue":"21","key":"e_1_2_8_16_1","doi-asserted-by":"crossref","DOI":"10.1182\/blood.V124.21.1071.1071","article-title":"CRLF2 over\u2010expression is a poor prognostic marker in children with high risk T\u2010cell acute lymphoblastic leukemia","volume":"124","author":"Palmi C","year":"2014","journal-title":"Blood"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2009.257"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-05-286492"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.10.035"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06866"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208353200"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002533"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semdp.2011.07.004"}],"container-title":["Pediatric Blood &amp; 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