RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
Nature communications - 8(2017), 1 vom: 19. Dez., Seite 2126 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lipka, Daniel B [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.10.2018 Date Revised 27.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-017-02177-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM279235224 |
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| 100 | 1 | |a Lipka, Daniel B |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia |
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| 500 | |a Date Revised 27.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML | ||
| 650 | 4 | |a Clinical Trial | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Observational Study | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
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| 700 | 1 | |a Witte, Tania |e verfasserin |4 aut | |
| 700 | 1 | |a Toth, Reka |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Wiesenfarth, Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Nöllke, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Fischer, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Brocks, David |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Zuguang |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Jeongbin |e verfasserin |4 aut | |
| 700 | 1 | |a Strahm, Brigitte |e verfasserin |4 aut | |
| 700 | 1 | |a Wlodarski, Marcin |e verfasserin |4 aut | |
| 700 | 1 | |a Yoshimi, Ayami |e verfasserin |4 aut | |
| 700 | 1 | |a Claus, Rainer |e verfasserin |4 aut | |
| 700 | 1 | |a Lübbert, Michael |e verfasserin |4 aut | |
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| 700 | 1 | |a Boerries, Melanie |e verfasserin |4 aut | |
| 700 | 1 | |a Hartmann, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Schönung, Maximilian |e verfasserin |4 aut | |
| 700 | 1 | |a Kilik, Umut |e verfasserin |4 aut | |
| 700 | 1 | |a Langstein, Jens |e verfasserin |4 aut | |
| 700 | 1 | |a Wierzbinska, Justyna A |e verfasserin |4 aut | |
| 700 | 1 | |a Pabst, Caroline |e verfasserin |4 aut | |
| 700 | 1 | |a Garg, Swati |e verfasserin |4 aut | |
| 700 | 1 | |a Catalá, Albert |e verfasserin |4 aut | |
| 700 | 1 | |a De Moerloose, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Dworzak, Michael |e verfasserin |4 aut | |
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