title: Expression analyses identify MLL as a prominent target of 11q23 amplification and support an etiologic role for MLL gain of function in myeloid malignancies.
abstract: MLL amplification was recently recognized as a recurrent aberration in acute myeloid leukemia (AML) and myelodys-plastic syndrome (MDS), associated with adverse prognosis and karyotype complexity. Here we present detailed results of fluorescence in situ hybridization (FISH) and expression analyses of MLL and 5 selected 11q candidate oncogenes (CBL, DDX6, ETS1, FLI1, and PLZF) in 31 patient samples and one cell line with 11q23 gain. FISH analyses revealed that the 11q23 amplicon invariably encompassed MLL, DDX6, ETS1, and FLI1, whereas expression analyses identified MLL and DDX6 as the most differentially expressed genes among samples with and without 11q23 copy gain or amplification. In MLL-amplified samples, a significant transcriptional up-regulation of MEIS1, PROML1, ADAM10, NKG2D, and ITPA was noted. Further analyses, designed to elucidate a possible role of the 11q overexpressed genes (MLL, DDX6, FLI1, and ETS1) in unselected MDS and AML samples, revealed a significant upregulation of MLL in MDS. Our findings confirm the MLL gene as a prominent target of 11q23 amplification and provide further evidence for an etiologic role for MLL gain of function in myeloid malignancies. In addition, our results indicate that the transcriptional program associated with MLL rearrangements and MLL overexpression displays significant similarities.
authors.affiliation: Centre for Medical Genetics, University Hospital Ghent, Belgium.
authors.forename: Bruce
authors.initials: B
authors.lastname: Poppe
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.forename: Claudia
authors.initials: C
authors.lastname: Schoch
authors.forename: Charlotta
authors.initials: C
authors.lastname: Lindvall
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrozek
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Lucienne
authors.initials: L
authors.lastname: Michaux
authors.forename: Nicole
authors.initials: N
authors.lastname: Dastugue
authors.forename: Christian
authors.initials: C
authors.lastname: Herens
authors.forename: Nurten
authors.initials: N
authors.lastname: Yigit
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Anne
authors.initials: A
authors.lastname: Hagemeijer
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D053487:DEAD-box RNA Helicases; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein; D050784:Proto-Oncogene Protein c-ets-1; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets; D011519:Proto-Oncogenes; D012316:RNA Nucleotidyltransferases / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C494041:ETS1 protein, human; C078433:FLI1 protein, human; C497422:KMT2A protein, human; D050784:Proto-Oncogene Protein c-ets-1; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D015534:Trans-Activators; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D012316:RNA Nucleotidyltransferases; C094683:DDX6 protein, human; D053487:DEAD-box RNA Helicases