title: Identification of new classes among acute myelogenous leukaemias with normal karyotype using gene expression profiling.
abstract: Conventional cytogenetic analysis currently stratifies acute myelogenous leukaemia (AML) into prognostically relevant groups. However, approximately 50% of adult AMLs have normal cytogenetics (NC-AMLs), and represent a heterogeneous and poorly understood group. We analysed gene expression in 55 AML samples including 53 cases from adult patients with NC-AML (n = 36), trisomy 8, t(15;17), t(8;21), t(11;19), 7q deletion, and two cell lines using 9000-gene DNA microarrays. Global hierarchical clustering showed that NC-AMLs are a heterogeneous group. Supervised analysis distinguished two subgroups of NC-AML: one subgroup constituted a homogeneous NC cluster ('pure NC-AML'), and the other NC-AMLs were close to the AML cases with translocations ('translocation like'). Gene expression signatures were also derived for patients with trisomy 8, as well as FLT3 and MLL gene duplications. Importantly, samples from 24 NC-AML patients who could be evaluated for clinical outcome were analysed. In all, 43 genes that discriminated two classes of patients with significantly different prognosis were identified. The poor prognosis class contained a majority of 'pure NC-AMLs', whereas the 'translocation-like' AMLs were in the good prognosis class. Discriminator genes included genes involved in drug resistance (TOP2B), protein transport (MTX2, SLC35A2), and cell signalling (MAPK1, PRKAB2). Our results demonstrate the transcriptional heterogeneity of NC-AMLs, and suggest the existence of 'translocation-like' NC-AMLs and of a gene expression signature that may predict response to chemotherapy.
authors.affiliation: Department of Molecular Oncology, Institut Paoli-Calmettes-UMR599 Inserm, IFR137, Marseille Cancer Institute, Marseille, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Marie-Joëlle
authors.initials: MJ
authors.lastname: Mozziconacci
authors.forename: Agnès
authors.initials: A
authors.lastname: Groulet-Martinec
authors.forename: Stéphane
authors.initials: S
authors.lastname: Debono
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.forename: Nadine
authors.initials: N
authors.lastname: Carbuccia
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Beillard
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Devilard
authors.forename: Christine
authors.initials: C
authors.lastname: Arnoulet
authors.forename: Diane
authors.initials: D
authors.lastname: Coso
authors.forename: Danielle
authors.initials: D
authors.lastname: Sainty
authors.forename: Luc
authors.initials: L
authors.lastname: Xerri
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Stoppa
authors.forename: Marina
authors.initials: M
authors.lastname: Lafage-Pochitaloff
authors.forename: Catherine
authors.initials: C
authors.lastname: Nguyen
authors.forename: Rémi
authors.initials: R
authors.lastname: Houlgatte
authors.forename: Didier
authors.initials: D
authors.lastname: Blaise
authors.forename: Dominique
authors.initials: D
authors.lastname: Maraninchi
authors.forename: Françoise
authors.initials: F
authors.lastname: Birg
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics; D020440:Gene Duplication; D020869:Gene Expression Profiling; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3