Low level CpG island promoter methylation predicts a poor outcome in adult T-cell acute lymphoblastic leukemia
Aurore Touzart,
Nicolas Boissel,
Mohamed Belhocine,
Charlotte Smith,
Carlos Graux,
Mehdi Latiri,
Ludovic Lhermitte,
Eve-Lyne Mathieu,
Françoise Huguet,
Laurence Lamant,
Pierre Ferrier,
Norbert Ifrah,
Elizabeth Macintyre,
Hervé Dombret,
Vahid Asnafi,
Salvatore Spicuglia
Affiliations
Aurore Touzart
Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France
Nicolas Boissel
Université Paris Diderot, Institut de Recherche Saint-Louis, EA-3518, Assistance Publique-Hôpitaux de Paris, University Hospital Saint-Louis, Hematology Department, Paris, France
Mohamed Belhocine
Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France;Aix-Marseille University, INSERM, TAGC, UMR 1090, Marseille, France;Equipe Labéllisée Ligue Contre le Cancer, Marseille, France
Charlotte Smith
Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France
Carlos Graux
Department of Hematology, Mont-Godinne University Hospital, Yvoir, Belgium
Mehdi Latiri
Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France
Ludovic Lhermitte
Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France
Eve-Lyne Mathieu
Aix-Marseille University, INSERM, TAGC, UMR 1090, Marseille, France;Equipe Labéllisée Ligue Contre le Cancer, Marseille, France
Françoise Huguet
Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
Laurence Lamant
Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
Pierre Ferrier
Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université UM2, Inserm, U1104, CNRS UMR7280, Marseille, France
Norbert Ifrah
PRES LUNAM, CHU Angers service des Maladies du Sang et INSERM U 892, Angers, France
Elizabeth Macintyre
Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France
Hervé Dombret
Université Paris Diderot, Institut de Recherche Saint-Louis, EA-3518, Assistance Publique-Hôpitaux de Paris, University Hospital Saint-Louis, Hematology Department, Paris, France
Vahid Asnafi
Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France
Salvatore Spicuglia
Aix-Marseille University, INSERM, TAGC, UMR 1090, Marseille, France;Equipe Labéllisée Ligue Contre le Cancer, Marseille, France
Cancer cells undergo massive alterations in their DNA methylation patterns which result in aberrant gene expression and malignant phenotypes. Abnormal DNA methylation is a prognostic marker in several malignancies, but its potential prognostic significance in adult T-cell acute lymphoblastic leukemia (T-ALL) is poorly defined. Here, we performed methylated DNA immunoprecipitation to obtain a comprehensive genome-wide analysis of promoter methylation in adult T-ALL (n=24) compared to normal thymi (n=3). We identified a CpG hypermethylator phenotype that distinguishes two T-ALL subgroups and further validated it in an independent series of 17 T-lymphoblastic lymphoma. Next, we identified a methylation classifier based on nine promoters which accurately predict the methylation phenotype. This classifier was applied to an independent series of 168 primary adult T-ALL treated accordingly to the GRAALL03/05 trial using methylation-specific multiplex ligation-dependent probe amplification. Importantly hypomethylation correlated with specific oncogenic subtypes of T-ALL and identified patients associated with a poor clinical outcome. This methylation-specific multiplex ligation-dependent probe amplification based methylation profiling could be useful for therapeutic stratification of adult T-ALL in routine practice. The GRAALL-2003 and -2005 studies were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.