We have previously reported on the importance of gene targeting by the Polycomb repressor complex 2 (PRC2) for the pathophysiology of multiple myeloma (MM) (Kalushkova et al. 2010; Agarwal et al. 2016; Alzrigat et al. 2017). This involved the generation of a ChIP-seq profile of Polycomb targeting as defined by H3K27me3 in primary MM cells and normal counterpart plasma cells from age-matched donors (Agarwal et al. 2016). Further analysis of the data now indicates that aberrant H3K27me3 targeting might extend further from genes to distal putative regulatory regions. Polycomb proteins are known to regulate nuclear organization and PRC2 has been shown to participate in the long-range contacts between poised enhancers, marked by H3K4me1 and H3K27me3, and the target genes in ESCs. Upon differentiation, these poised enhancers exchange H3K27me3 by H3K27ac, becoming active in regulating their target genes (Cruz-Molina, Respuela et al. 2017). This prompts us to now define active enhancers in the normal counterpart to evaluate the possible decommissioning of these in the transformation to MM. This project is a continuation of project b2011152. Furthermore, this project will contain data on infant acute lymphoblastic leukaemia (iALL), which is a rare haematological disease, comprising less than 5% of all childhood ALL cases. Translocation in the mixed-lineage leukaemia gene (MLL/KMT2A) are found in 75% of iALL cases. Notably, the KMT2A rearrangement (KMT2A-r) has been strongly associated with a poorer prognosis and disease relapse in iALL. It is imperative to understand the underlying mechanisms contributing to drug resistance and disease progression in iALL. In this study, we utilized rule-based machine learning to investigate the differences between iALL harbouring KMT2A-r and paediatric ALL with KMT2A-germline. We identified a distinctive iALL KMT2A-r network comprised by predominantly downregulated genes. Additionally, scRNA-seq was utilized as validation of the unique iALL KMT2A-r gene signature in our own iALL cohort. Furthermore, we could demonstrate that 36% of the top 50 genes unique to iALL KMT2A-r are potentially marked with H3K27me3, suggesting that the silenced profile might result from dysregulated EZH2 function. Further treatment with the EZH2 inhibitor UNC1999, led to cells death in a iALL KMT2A-r cell line. Taken together, our data, albeit preliminary, suggests that this approach holds great potential for identifying new therapeutic targets in iALL.