Epigenetic analysis of patients with T-ALL identifies poor outcomes and a hypomethylating agent-responsive subgroup

Aurore Touzart, Anand Mayakonda, Charlotte Smith, Joschka Hey, Reka Toth, Agata Cieslak, Guillaume P. Andrieu, Christine Tran Quang, Mehdi Latiri, Jacques Ghysdael, Salvatore Spicuglia, Hervé Dombret, Norbert Ifrah, Elizabeth Macintyre, Pavlo Lutsik, Nicolas Boissel, Christoph Plass, Vahid Asnafi*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

Adult "T cell" acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is associated with poor outcomes, requiring additional therapeutic options. The DNA methylation landscapes of adult T-ALL remain undercharacterized. Here, we systematically analyzed the DNA methylation profiles of normal thymic-sorted T cell subpopulations and 143 primary adult T-ALLs as part of the French GRAALL 2003-2005 trial. Our results indicated that T-ALL is epigenetically heterogeneous consisting of five subtypes (C1-C5), which were either associated with co-occurring DNA methyltransferase 3 alpha (DNMT3A)/isocitrate dehydrogenase [NADP(+)] 2 (IDH2) mutations (C1), TAL bHLH transcription factor 1, erythroid differentiation factor (TAL1) deregulation (C2), T cell leukemia homeobox 3 (TLX3) (C3), TLX1/in cis-homeobox A9 (HOXA9) (C4), or in trans-HOXA9 overexpression (C5). Integrative analysis of DNA methylation and gene expression identified potential cluster-specific oncogenes and tumor suppressor genes. In addition to an aggressive hypomethylated subgroup (C1), our data identified an unexpected subset of hypermethylated T-ALL (C5) associated with poor outcome and primary therapeutic response. Using mouse xenografts, we demonstrated that hypermethylated T-ALL samples exhibited therapeutic responses to the DNA hypomethylating agent 5-azacytidine, which significantly (survival probability; P = 0.001 for C3, 0.01 for C4, and 0.0253 for C5) delayed tumor progression. These findings suggest that epigenetic-based therapies may provide an alternative treatment option in hypermethylated T-ALL.

Original languageEnglish
Article numbereabc4834
JournalScience Translational Medicine
Volume13
Issue number595
DOIs
Publication statusPublished - 26 May 2021
Externally publishedYes

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