A Novel Inducible Mouse Model of -driven Mixed-lineage Acute Leukemia.

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 "" 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. leukemic cells generally expressed lower mRNA than those obtained after retroviral transduction. Disease induction was associated with levels exceeding the endogenous at mRNA and protein levels. In leukemic cells from t(11;19) leukemia patients, mRNA also exceeded the endogenous levels suggesting a critical threshold for transformation. Expression profiling of acute leukemia revealed gene signatures that segregated t(11;19) leukemia patients from those without an MLL translocation. Importantly, B220 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 -driven acute leukemia.