Haematologica (Jun 2020)

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

DOI
https://doi.org/10.3324/haematol.2019.223677
Journal volume & issue
Vol. 105, no. 6

Abstract

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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.