Despite extensive efforts to model infant and childhood B-ALL, including ETV6-RUNX1, in mice (Schindler et al., 2009, van der Weyden et al., 2011), these have so far provided limited insight into the earliest stages of pre-leukemic initiation and failed to faithfully recapitulate the lymphoid disease, highlighting the need to explore developmentally relevant human model systems. Here, ETV6 is linked to precursor B-cell acute lymphoblastic leukemia.