Epigenetic analysis of patients with T-ALL identifies poor outcomes and a hypomethylating agent-responsive subgroup.
Aurore TouzartAnand MayakondaCharlotte L SmithJoschka HeyReka TothAgata CieslakGuillaume P AndrieuChristine Tran QuangMehdi LatiriJacques GhysdaelSalvatore SpicugliaHervé DombretNorbert IfrahElizabeth A MacintyrePavlo LutsikNicolas BoisselChristoph PlassVahid AsnafiPublished in: Science translational medicine (2021)
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.
Keyphrases
- dna methylation
- genome wide
- gene expression
- transcription factor
- acute lymphoblastic leukemia
- circulating tumor
- phase iii
- long noncoding rna
- cell free
- single molecule
- long non coding rna
- clinical trial
- copy number
- poor prognosis
- bone marrow
- childhood cancer
- type diabetes
- study protocol
- dna binding
- genome wide identification
- acute myeloid leukemia
- cell proliferation
- drug delivery
- phase ii
- randomized controlled trial
- artificial intelligence
- machine learning
- adipose tissue
- metabolic syndrome
- data analysis