Acute myeloid leukemia (AML) is characterized by aberrant signal transduction resulting in enhanced cell survival, proliferation and resistance to apoptotic cell death. Rewired signaling is caused by acquired genetic alterations and/or by overexpression/aberrant expression of signal transduction molecules. Whereas canonical signal transduction initiates transcription factor activation and target gene expression, recent reports have also shown profound effects on chromatin modification and regulation of DNA damage response and repair. Of note, disturbed signal transduction in cancer cells results in tumor specific alterations associated with aberrant self-renewal and stress response but also synthetic vulnerability. Against this background we aim to dissect the influence of defined alterations within signal transduction pathways on epigenetic modifications, DNA repair and resistance to genotoxic agents/small molecule inhibitors. To address this question, we take advantage of a broad spectrum of mouse models. In addition, we have created several isogenic cell culture models using siRNA mediated gene knockdown or CRISPR-Cas9-mediated knockout. Further, cancer cells will be treated with specific small molecule inhibitors targeting signal transduction proteins. The impact on DNA damage response and repair will be explored by applying qRT-based gene expression analyses and in vivo DNA repair assays. Based on these technologies we hope to identify novel treatment strategies combining inhibitors that target DNA damage repair pathways, epigenetic modifiers and signal transduction molecules.