Prognostic relevance of disordered epigenetic regulation in juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of early childhood which takes a fatal course in most cases unless treated with hematopoietic stem cell transplantation. We recently provided evidence for epigenetic dysregulation in JMML and showed that aberrant DNA methylation at defined loci strongly correlates with disease progression and outcome. We have now extended the methylation analysis to genome-wide scale (MCIp-Seq) and find that unsupervised clustering based on aberrantly methylated DNA fragments robustly identifies two patient clusters. To obtain a quantitative high-resolution profile of epigenetic dysregulation in JMML, we currently perform mass spectrometry (MassARRAY) for CpG methylation at 45 candidate genes with relevance to myeloid malignant disease. In addition, we are assessing concurrent histone modifications at target sites of aberrant DNA methylation in JMML such as BMP4, CDKN2B and RARB. In summary, our data lend further support to the existence of a methylator phenotype in JMML with stronger predictive value for disease course than genetic lesions such as Ras pathway mutations.