Page 117 - Haematologica - Vol. 105 n. 6 - June 2020

Acute Lymphoblastic Leukemia
Low level CpG island promoter methylation predicts a poor outcome in adult T-cell acute lymphoblastic leukemia
Aurore Touzart,1 Nicolas Boissel,2 Mohamed Belhocine,1,3,4 Charlotte Smith,1 Carlos Graux,5 Mehdi Latiri,1 Ludovic Lhermitte,1 Eve-Lyne Mathieu,3,4 Françoise Huguet,6 Laurence Lamant,7 Pierre Ferrier,8 Norbert Ifrah,9 Elizabeth Macintyre,1 Hervé Dombret,2 Vahid Asnafi1 and Salvatore Spicuglia3,4
1Université 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; 2Université Paris Diderot, Institut de Recherche Saint-Louis, EA-3518, Assistance Publique-Hôpitaux de Paris, University Hospital Saint-Louis, Hematology Department, Paris, France; 3Aix-Marseille University, INSERM, TAGC, UMR 1090, Marseille, France; 4Equipe Labéllisée Ligue Contre le Cancer, Marseille, France; 5Department of Hematology, Mont-Godinne University Hospital, Yvoir, Belgium; 6Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France; 7Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France; 8Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université UM2, Inserm, U1104, CNRS UMR7280, Marseille, France and 9PRES LUNAM, CHU Angers service des Maladies du Sang et INSERM U 892, Angers, France
ABSTRACT
Cancer cells undergo massive alterations in their DNA methylation patterns which result in aberrant gene expression and malignant phe- notypes. Abnormal DNA methylation is a prognostic marker in sev- eral malignancies, but its potential prognostic significance in adult T-cell acute lymphoblastic leukemia (T-ALL) is poorly defined. Here, we per- formed methylated DNA immunoprecipitation to obtain a comprehensive genome-wide analysis of promoter methylation in adult T-ALL (n=24) com- pared to normal thymi (n=3). We identified a CpG hypermethylator pheno- type 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 amplifica- tion. Importantly hypomethylation correlated with specific oncogenic sub- types of T-ALL and identified patients associated with a poor clinical out- come. This methylation-specific multiplex ligation-dependent probe ampli- fication based methylation profiling could be useful for therapeutic stratifi- cation of adult T-ALL in routine practice. The GRAALL-2003 and -2005 stud- ies were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.
Introduction
T-cell acute lymphoblastic leukemias (T-ALL) are aggressive and heterogeneous malignancies which are predominated by the 10-39-year age group where they account for 20% of acute lymphoblastic leukemias (ALL).1 T-ALL is associated with a wide range of acquired genetic abnormalities that contribute to developmental arrest and abnormal proliferation of malignant lymphoid progenitors.2,3 Despite the diversity of observed mutations and deletions, genome wide expression4-6 assays led to the identification of few oncogenic T-ALL subgroups, namely the imma-
Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1575-1581
Correspondence:
SALVATORE SPICUGLIA
salvatore.spicuglia@inserm.fr
VAHID ASNAFI
vahid.asnafi@nck.aphp.fr
Received: April 4, 2019.
Accepted: September 19, 2019. Pre-published: September 19, 2019.
doi:10.3324/haematol.2019.223677
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/106/6/1575
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