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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.

RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia