A novel inducible mouse model of MLL-ENL -driven mixed-lineage acute leukemia

Vaia Stavropoulou, Marwa Almosailleakh, Hélène Royo, Jean François Spetz, Sabine Juge, Laurent Brault, Patrick Kopp, Michelina Iacovino, Michael Kyba, Alexandar Tzankov, Michael B. Stadler, Gianni Cazzaniga, Antoine H.F.M. Peters, Juerg Schwaller

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere51
JournalHemaSphere
Volume2
Issue number4
DOIs
StatePublished - Aug 1 2018

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