TY  - JOUR
AU  - Lipka, Daniel B
AU  - Witte, Tania
AU  - Toth, Reka
AU  - Yang, Jing
AU  - Wiesenfarth, Manuel
AU  - Nöllke, Peter
AU  - Fischer, Alexandra
AU  - Brocks, David
AU  - Gu, Zuguang
AU  - Park, Jeongbin
AU  - Strahm, Brigitte
AU  - Wlodarski, Marcin
AU  - Yoshimi, Ayami
AU  - Claus, Rainer
AU  - Lübbert, Michael
AU  - Busch, Hauke
AU  - Boerries, Melanie
AU  - Hartmann, Mark
AU  - Schönung, Maximilian
AU  - Kilik, Umut
AU  - Langstein, Jens
AU  - Wierzbinska, Justyna A
AU  - Pabst, Caroline
AU  - Garg, Swati
AU  - Catalá, Albert
AU  - De Moerloose, Barbara
AU  - Dworzak, Michael
AU  - Hasle, Henrik
AU  - Locatelli, Franco
AU  - Masetti, Riccardo
AU  - Schmugge, Markus
AU  - Smith, Owen
AU  - Stary, Jan
AU  - Ussowicz, Marek
AU  - van den Heuvel-Eibrink, Marry M
AU  - Assenov, Yassen
AU  - Schlesner, Matthias
AU  - Niemeyer, Charlotte
AU  - Flotho, Christian
AU  - Plass, Christoph
TI  - RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia.
JO  - Nature Communications
VL  - 8
IS  - 1
SN  - 2041-1723
CY  - London
PB  - Nature Publishing Group
M1  - DKFZ-2017-06275
SP  - 2126
PY  - 2017
N1  - (* Co-first authors)
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29259247
C2  - pmc:PMC5736667
DO  - DOI:10.1038/s41467-017-02177-w
UR  - https://inrepo02.dkfz.de/record/131643
ER  -