Identification of new classes among acute myelogenous leukaemias with normal karyotype using gene expression profiling.
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.
Vey
Norbert
N
Department of Molecular Oncology, Institut Paoli-Calmettes-UMR599 Inserm, IFR137, Marseille Cancer Institute, Marseille, France.
Mozziconacci
Marie-Joëlle
MJ
Groulet-Martinec
Agnès
A
Debono
Stéphane
S
Finetti
Pascal
P
Carbuccia
Nadine
N
Beillard
Emmanuel
E
Devilard
Elizabeth
E
Arnoulet
Christine
C
Coso
Diane
D
Sainty
Danielle
D
Xerri
Luc
L
Stoppa
Anne-Marie
AM
Lafage-Pochitaloff
Marina
M
Nguyen
Catherine
C
Houlgatte
Rémi
R
Blaise
Didier
D
Maraninchi
Dominique
D
Birg
Françoise
F
Birnbaum
Daniel
D
Bertucci
François
F
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
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