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Previous retroviral and knock-in approaches to model human t(11;19)+ acute mixed-lineage leukemia in mice resulted in myeloproliferation and acute myeloid leukemia not fully recapitulating the human disease. The authors established a doxycycline (DOX)-inducible transgenic mouse model “iMLL-ENL” in which induction in long-term hematopoietic stem cells, lymphoid primed multipotent progenitor cells, multipotent progenitors (MPP4) but not in more committed myeloid granulocyte-macrophage progenitors led to a fully reversible acute leukemia expressing myeloid and B-cell markers. iMLL-ENL leukemic cells generally expressed lower MLL-ENL mRNA than those obtained after retroviral transduction. Disease induction was associated with iMLL-ENL levels exceeding the endogenous Mll1 at mRNA and protein levels. In leukemic cells from t(11;19)+ leukemia patients, MLL-ENL mRNA also exceeded the endogenous MLL1 levels suggesting a critical threshold for transformation. Expression profiling of iMLL-ENL acute leukemia revealed gene signatures that segregated t(11;19)+ leukemia patients from those without an MLL translocation. Importantly, B220+iMLL-ENL leukemic cells showed a higher in vivo leukemia initiation potential than coexisting B220− cells. Collectively, characterization of a novel transgenic mouse model indicates that the cell-of-origin and the fusion gene expression levels are both critical determinants for MLL-ENL-driven acute leukemia.