The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and functional core subunit of the polycomb repressive complex 2 (PRC2), which is a key epigenetic regulator involved in embryonic development and transcriptional repression of genes by catalyzing the methylation of histone H3 at lysine 27 (H3K27me2/3). EZH2 overexpression has been associated with oncogenic activity and worse progression-free survival in several types of cancer including lymphoma, melanoma, prostate and breast cancer.2 Moreover, the detection of recurrent EZH2 mutations, both gain-of-function in lymphomas and loss-of-function in e.g. in medulloblastoma, bladder and renal cancers, point to a mutual role of EZH2 for disease pathology depending on the distinct type of cancer and indicate the potential of EZH2 as a therapeutic target. In myeloid malignancies such as myelodysplastic syndromes (MDS), loss of EZH2 activity by inactivating mutations is associated with poor prognosis. More recently, EZH2 inactivation by post translational modification was shown to induce chemoresistance in acute myeloid leukemia (AML). However, data on the frequency and prognostic role of EZH2 mutations in AML are still scarce and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations.