Since self-renewal without the capacity to differentiate characterizes a premalignant state, we reasoned that Rpl22−/− HSCs should be predisposed to leukemic transformation.40 Consequently, we assessed whether Rpl22−/− HSCs were predisposed to transformation using the MLL-AF9 oncogene knockin model of AML.41,42 Indeed, MLL-AF9 knockin mice exhibited splenomegaly comprising Mac1+ leukemic cells (Figure S3A), with the Rpl22−/− mice exhibiting a far greater leukemic burden at 15 weeks of age, as shown by splenic weight (Figure 4A). Here, KMT2A is linked to acute myeloid leukemia.