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    Nature communications. 2017 Dec 19. doi: 10.1038/s41467-017-02177-w. pii: 10.1038/s41467-017-02177-w
    RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia.
    Lipka DB1,  Witte T2,  Toth R3,  Yang J4,  Wiesenfarth M5,  Nöllke P6,  Fischer A7,  Brocks D8,  Gu Z9,  Park J10,  Strahm B11,  Wlodarski M12,  Yoshimi A13,  Claus R14,  Lübbert M15,  Busch H16,  Boerries M17,  Hartmann M18,  Schönung M19,  Kilik U20,  Langstein J21,  Wierzbinska JA22,  Pabst C23,  Garg S24,  Catalá A25,  De Moerloose B26,  Dworzak M27,  Hasle H28,  Locatelli F29,  Masetti R30,  Schmugge M31,  Smith O32,  Stary J33,  Ussowicz M34,  van den Heuvel-Eibrink MM35,  Assenov Y36,  Schlesner M37,  Niemeyer C38,  Flotho C39,  Plass C40
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    Abstract

    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.


    Publikations ID: 29259247
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