Juvenile myelomonocytic leukemia (JMML) is a complex and rare pediatric cancer with an aggressive clinical course. Despite the identification of 5 genetic subtypes, our current understanding falls short in fully capturing the phenotypic and prognostic heterogeneity observed among patients. Consequently, research is now exploring epigenomics and transcriptomics to understand gene activity. Notably, DNA methylation has emerged as the current most reliable predictor of clinical outcome in JMML. In this project I aim to expand our understanding of epigenetic mechanisms in JMML to the field of histone post translational modifications (hPTMs). These hPTMs are crucial regulators of gene function. I will also delve deeper into the translation of mRNA into proteins, as this is where the disease phenotype truly arises. Inclusion of proteomics offers a complementary dimension, potentially providing unprecedented insights into JMML pathobiology. Ultimately, I will perform a thorough integration of clinical, genomic, epigenomic, transcriptomic and proteomic data for a well selected cohort of JMML patients. Such a comprehensive multi-omics approach will allow refinement of JMML subtypes based on the underlying biological mechanisms and clinical outcomes. This finer-scale subtyping is part of a growing trend in cancer research towards personalized medicine. A deeper understanding of JMML pathobiology will enhance our ability to predict its clinical course and tailor treatment strategies.