1. ¹Department of Molecular Oncology, Institut Paoli-Calmettes-UMR599 Inserm, IFR137, Marseille Cancer Institute, Marseille, France
2. ²Department of Haematology, Institut Paoli-Calmettes-UMR599 Inserm, IFR137, Marseille Cancer Institute, Marseille, France
3. ³Department of BioPathology, Institut Paoli-Calmettes-UMR599 Inserm, IFR137, Marseille Cancer Institute, Marseille, France
4. ⁴IPSOGEN SAS, Marseille, France
5. ⁵ERT MEIDIA, Marseille, France
6. ⁶Université of Méditerranée, Marseille, France
7. ⁷ERM206, Marseille, France

Correspondence: D Birnbaum, UMR599 Inserm, 27 Bd. Leï Roure, Marseille 13009, France. E-mail: birnbaum@marseille.inserm.fr

Received 15 March 2004; Revised 18 March 2004; Accepted 26 May 2004; Published online 15 November 2004.

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.