title: Amplification and translocation of 3q26 with overexpression of EVI1 in Fanconi anemia-derived childhood acute myeloid leukemia with biallelic FANCD1/BRCA2 disruption.
abstract: Fanconi anemia (FA) is an inherited disease with congenital abnormalities and an extreme risk of acute myeloid leukemia (AML). Genetic events occurring during malignant transformation in FA and the biology of FA-associated AML are poorly understood, but are often preceded by the development of chromosomal aberrations involving 3q26-29 in bone marrow of FA patients. We report here the molecular cytogenetic characterization of FA-derived AML cell lines SB1685CB and SB1690CB by conventional and array comparative genomic hybridization, fluorescence in situ hybridization, and SKY. We identified gains of a 3.7 MB chromosomal region on 3q26.2-26.31, which preceded transformation to overt leukemia. This region harbors the oncogenic transcription factor EVI1. A third FA-derived cell line, FA-AML1, carried a translocation with ectopic localization of 3q26 including EVI1. Rearrangements of 3q, which are rare in childhood AML, commonly result in overexpression of EVI1, which determines specific gene expression patterns and confers poor prognosis. We detected overexpression of EVI1 in all three FA-derived AML. Our results suggest a link between the FA defect, chromosomal aberrations involving 3q and overexpression of EVI1. We hypothesize that constitutional or acquired FA defects might be a common factor for the development of 3q abnormalities in AML. In addition, cryptic imbalances as detected here might account for overexpression of EVI1 in AML without overt 3q26 rearrangements.
authors.affiliation: Academic Unit of Paediatric Oncology, Christie Hospital Trust, University of anchester, Manchester, UK. stefan.meyer@manchester.ac.uk
authors.forename: Stefan
authors.initials: S
authors.lastname: Meyer
authors.forename: William D
authors.initials: WD
authors.lastname: Fergusson
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Whetton
authors.forename: Flavia
authors.initials: F
authors.lastname: Moreira-Leite
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Pepper
authors.forename: Crispin
authors.initials: C
authors.lastname: Miller
authors.forename: Emma K
authors.initials: EK
authors.lastname: Saunders
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: White
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Will
authors.forename: Tim
authors.initials: T
authors.lastname: Eden
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ikeda
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ullmann
authors.forename: Seval
authors.initials: S
authors.lastname: Tuerkmen
authors.forename: Antje
authors.initials: A
authors.lastname: Gerlach
authors.forename: Eva
authors.initials: E
authors.lastname: Klopocki
authors.forename: Holger
authors.initials: H
authors.lastname: Tönnies
mesh_terms: D000208:Acute Disease; D024682:BRCA2 Protein / Q000235:genetics*; D002460:Cell Line; D002648:Child; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005199:Fanconi Anemia / Q000235:genetics*; D005784:Gene Amplification; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D000074008:MDS1 and EVI1 Complex Locus Protein; D011519:Proto-Oncogenes / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors