The first epigenetic targeting drugs (DNMT and HDAC inhibitors) have efficacy in some types of cancer but are limited by either target related or side effect toxicity. The full potential of epigenetic based therapies has not yet been fully realised due both to the limitations of biological knowledge on specific targets and to defective strategies in current drug discovery approaches based on recombinant, single target assays. Although deregulated expression of a few epi-targets has been found in cancer, functional results are required to determine which of them would qualify as candidate drug targets. Thus, BLUEPRINT utilises novel RNAi screens to validate epigenetic targets in ex vivo and in vivo settings. Particularly relevant is the concept of direct in vivo validation of candidate epigenetic targets, an approach that has not been tried before on a selected set of candidate drug targets. We will perform immediately the in vivo RNAi based screens in murine leukaemia models and patient derived human samples, in order to achieve the most relevant level of preclinical validation possible. Cell assays and screens will be a complement to the in vivo screens, and will be used for further validation, and -most importantly- for further characterization of the biological phenotypes, and to provide assays for the drug discovery process. Thus, the conventional process of gradual validation (from in vitro to in vivo studies) will be subverted, and an innovative strategy will be aggressively pursued.