We identified common recurrent mutations in known T-ALL genes (e.g. NOTCH1, PHF6, FBXW7 and JAK3) as well as novel somatic mutations in genes involved in RNA splicing (U2AF1), chromatin remodeling (KMT2C/MLL3) and of particular interest given the observed male gender bias, in X-linked genes MED12 and USP9X. Additional functional studies provide evidence of the potential implication of these newly identified mutations in childhood T-ALL pathogenesis. Here, U2AF1 is linked to acute lymphoblastic leukemia.