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 (C₁-C₅), which were either associated with co-occurring <i>DNA methyltransferase 3 alpha</i> (<i>DNMT3A</i>)/<i>isocitrate dehydrogenase</i> [<i>NADP</i>(<i>+</i>)] <i>2</i> (<i>IDH2</i>) mutations (C₁), <i>TAL bHLH transcription factor 1</i>, <i>erythroid differentiation factor</i> (<i>TAL1</i>) deregulation (C₂), <i>T cell leukemia homeobox 3</i> (<i>TLX3</i>) (C₃), <i>TLX1</i>/in <i>cis</i>-<i>homeobox A9</i> (<i>HOXA9</i>) (C₄), or in <i>trans</i>-<i>HOXA9</i> 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; <i>P</i> = 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.