We propose here a focused effort in strengthening epigenomics research in Sweden. Specifically, we want to build on our joint expertise to bridge pre-clinical and clinical research with a focus on a human disease that displays a high mortality prompting a new perspective: Acute Myeloid Leukemia (AML). This disease involves tumor stem cells that we have hypothesized to display extensive epigenetic mutations (Feinberg, Ohlsson et al, Nature rev genet 2006 [1]). To explore this link, we will study both chromatin marks (reviewed in Lennartsson, Ekwall BBA 2009 [2]) and higher order conformations (Göndör and Ohlsson, Nature 2009 [3]) in AML stem cells and derived tumor cells with the aim to develop novel prognostic tools predicting the course of the disease. This is important as changes in epigenetic marks/higher order chromatin conformations in stem cells predate overt changes in gene expression patterns to enable a diagnosis much earlier than by any conventional method. Thus it was recently shown that epigenomic profiling of one repressive histone mark (H3K9me3) predicts survival in AML (Muller-Tidow Blood 2010 [4]). Moreover, our data show that DNA methylation patterns are an important predictor of prognosis in AML (Deneberg & Lehmann, Leukemia 2010 [5]). We thus hypothesize that different chromatin marks and higher order chromatin structures provide a pathological pin code that enables a much earlier and more accurate staging of the disease. In addition, our proposal may lead to therapeutic strategies targeting epimutations to promote an enhanced survival and eventually a complete remission of affected patients. We believe that this strategy might provide a paradigm shift in how epigenomics can be used to understand and treat human diseases.