title: Molecular characterization of acute lymphoblastic leukemia with high CRLF2 gene expression in childhood.
abstract: BACKGROUND
  A high-level expression of the CRLF2 gene is frequent in precursor B-cell acute lymphoblastic leukemia (pB-ALL) and can be caused by different genetic aberrations. The presence of the most frequent alteration, the P2RY8/CRLF2 fusion, was shown to be associated with a high relapse incidence in children treated according to ALL-Berlin-Frankfurt-Münster (BFM) protocols, which is poorly understood. Moreover, the frequency of other alterations has not been systematically analyzed yet.
  
  
  METHODS
  CRLF2 mRNA expression and potential genetic aberrations causing a CRLF2 high expression were prospectively assessed in 1,105 patients treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)-BFM ALL 2009 protocol. Additionally, we determined copy number alterations in selected B-cell differentiation genes for all CRLF2 high-expressing pB-ALL cases, as well as JAK2 and CRLF2 mutations.
  
  
  RESULTS
  A CRLF2 high expression was detected in 26/178 (15%) T-cell acute lymphoblastic leukemia (T-ALL) cases, 21 of them (81%) had been stratified as high-risk patients by treatment response. In pB-ALL, a CRLF2 high expression was determined in 91/927 (10%) cases; the P2RY8/CRLF2 rearrangement in 44/91 (48%) of them, supernumerary copies of CRLF2 in 18/91 (20%), and, notably, the IGH/CRLF2 translocation was detected in 16/91 (18%). Remarkably, 7 of 16 (44%) patients with IGH/CRLF2 translocation had already relapsed. P2RY8/CRLF2- and IGH/CRLF2-positive samples (70 and 94%, respectively) were characterized by a high frequency of additional deletions in B-cell differentiation genes such as IKZF1 or PAX5.
  
  
  CONCLUSIONS
  Our data suggest that this high frequency of genetic aberrations in the context of a high CRLF2 expression could contribute to the high risk of relapse in P2RY8/CRLF2- and IGH/CRLF2-positive ALL.
authors.affiliation: Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Schmäh
authors.affiliation: Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Birthe
authors.initials: B
authors.lastname: Fedders
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Panzer-Grümayer
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Susanna
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Elif
authors.initials: E
authors.lastname: Dagdan
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Medical Center Schleswig-Holstein, Kiel, Germany.|Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Bens
authors.affiliation: Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Denis
authors.initials: D
authors.lastname: Schewe
authors.affiliation: Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Moericke
authors.affiliation: Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Alten
authors.affiliation: Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Bleckmann
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Medical Center Schleswig-Holstein, Kiel, Germany.|Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Department of Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001215:Asparaginase / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D003630:Daunorubicin / Q000008:administration & dosage; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D015321:Gene Rearrangement; D006801:Humans; D051740:Ikaros Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D007223:Infant; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics; D051757:PAX5 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011241:Prednisone / Q000008:administration & dosage; D018121:Receptors, Cytokine / Q000096:biosynthesis* / Q000235:genetics; D058470:Receptors, Purinergic P2Y / Q000096:biosynthesis / Q000235:genetics; D014750:Vincristine / Q000008:administration & dosage
chemical_list: C498762:CRLF2 protein, human; C497239:IKZF1 protein, human; D015514:Oncogene Proteins, Fusion; C578279:P2RY8 protein, human; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D018121:Receptors, Cytokine; D058470:Receptors, Purinergic P2Y; D051740:Ikaros Transcription Factor; D014750:Vincristine; D001215:Asparaginase; D011241:Prednisone; D003630:Daunorubicin
keywords: CRLF2; IGH/CRLF2; P2RY8/CRLF2; acute lymphoblastic leukemia; prognosis