Gene mutations do not operate in a vacuum: the increasing importance of epigenetics in juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) stands out among malignant neoplasms of childhood in several ways. First, JMML is a model condition to elucidate the relevance of deregulated Ras signal transduction in human cancer. Second, the identification of Ras pathway mutations in JMML has informed the field of germline cancer predisposition and advanced the understanding of molecular mechanisms underlying the progression from predisposition to neoplasia. Third and not least, genomic DNA methylation was discovered to play a salient role in the classification and prognostication of the disease. This article discusses the evolution of epigenetic research on JMML over the past years and reviews the relevance of aberrant DNA methylation in the diagnosis, concept, and clinical decision-making of JMML.