Open AccessLow level CpG island promoter methylation predicts a poor outcome in adult T-cell acute lymphoblastic leukemia
Author(s) -
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
Publication year - 2019
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2019.223677
Subject(s) - methylation , dna methylation , cpg site , biology , cancer research , microbiology and biotechnology , promoter , multiplex , gene , genetics , gene expression
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.