Dorit Schneider from Hannover Medical School, Hannover, Germany, describes her work on oncogenic mutational networks in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) at the International Symposium on Acute Leukemias (ISAL) 2017 in Munich, Germany. She explains that patients usually have 3-5 separate mutations, and highlights the importance of identifying interactions in whole mutational networks. Loss of function mutations in EZH2 are common in both AML and MDS. Dorit Schneider describes how she established CRISPR-Cas9 cooperation screening in vitro and in vivo, and explains how the transforming and leukemogenic potential of different combinations of guide RNAs in addition to the EZH2 guide RNA were measured. She summarizes that in vivo, loss of function of the genes Nf1, Dnmt3 and Runx1 has a cooperative effect with EZH2 loss, while Stag2 loss of function mutation is dispensable for induction of EZH2 loss of function in acute myeloid leukemia.