Epigenetic analysis of patients with T-ALL identifies poor outcomes and a hypomethylating agent-responsive subgroup
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Science translational medicine - 13(2021), 595 vom: 26. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Touzart, Aurore [VerfasserIn] |
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| Links: |
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| Themen: |
Clinical Trial |
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| Anmerkungen: |
Date Completed 12.07.2021 Date Revised 31.05.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1126/scitranslmed.abc4834 |
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| Förderinstitution / Projekttitel: |
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NLM325886369 |
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| 520 | |a 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 | ||
| 650 | 4 | |a Clinical Trial | |
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| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 700 | 1 | |a Mayakonda, Anand |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Charlotte |e verfasserin |4 aut | |
| 700 | 1 | |a Hey, Joschka |e verfasserin |4 aut | |
| 700 | 1 | |a Toth, Reka |e verfasserin |4 aut | |
| 700 | 1 | |a Cieslak, Agata |e verfasserin |4 aut | |
| 700 | 1 | |a Andrieu, Guillaume P |e verfasserin |4 aut | |
| 700 | 1 | |a Tran Quang, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Latiri, Mehdi |e verfasserin |4 aut | |
| 700 | 1 | |a Ghysdael, Jacques |e verfasserin |4 aut | |
| 700 | 1 | |a Spicuglia, Salvatore |e verfasserin |4 aut | |
| 700 | 1 | |a Dombret, Hervé |e verfasserin |4 aut | |
| 700 | 1 | |a Ifrah, Norbert |e verfasserin |4 aut | |
| 700 | 1 | |a Macintyre, Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Lutsik, Pavlo |e verfasserin |4 aut | |
| 700 | 1 | |a Boissel, Nicolas |e verfasserin |4 aut | |
| 700 | 1 | |a Plass, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Asnafi, Vahid |e verfasserin |4 aut | |
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