Epigenetic Analysis Of Patients With T-All Identifies Poor Outcomes And A Hypomethylating Agent-Responsive Subgroup

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.