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

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 (C 1 -C 5 ), which were either associated with co-occurring DNA methyltransferase 3 alpha ( DNMT3A )/ isocitrate dehydrogenase [ NADP ( + )] 2 ( IDH2 ) mutations (C 1 ), TAL bHLH transcription factor 1 , erythroid differentiation factor ( TAL1 ) deregulation (C 2 ), T cell leukemia homeobox 3 ( TLX3 ) (C 3 ), TLX1 /in cis - homeobox A9 ( HOXA9 ) (C 4 ), or in trans - HOXA9 overexpression (C 5 ). Integrative analysis of DNA methylation and gene expression identified potential cluster-specific oncogenes and tumor suppressor genes. In addition to an aggressive hypomethylated subgroup (C 1 ), our data identified an unexpected subset of hypermethylated T-ALL (C 5 ) 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 C 3 , 0.01 for C 4 , and 0.0253 for C 5 ) delayed tumor progression. These findings suggest that epigenetic-based therapies may provide an alternative treatment option in hypermethylated T-ALL.
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Submitted on : Friday, July 9, 2021 - 3:36:08 PM
Last modification on : Tuesday, October 19, 2021 - 10:50:26 PM




Aurore Touzart, Anand Mayakonda, Charlotte Smith, Joschka Hey, Reka Toth, et al.. Epigenetic analysis of patients with T-ALL identifies poor outcomes and a hypomethylating agent-responsive subgroup. Science Translational Medicine, American Association for the Advancement of Science, 2021, 13 (595), pp.eabc4834. ⟨10.1126/scitranslmed.abc4834⟩. ⟨hal-03282998⟩



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