TY - JOUR
T1 - A novel inducible mouse model of MLL-ENL -driven mixed-lineage acute leukemia
AU - Stavropoulou, Vaia
AU - Almosailleakh, Marwa
AU - Royo, Hélène
AU - Spetz, Jean François
AU - Juge, Sabine
AU - Brault, Laurent
AU - Kopp, Patrick
AU - Iacovino, Michelina
AU - Kyba, Michael
AU - Tzankov, Alexandar
AU - Stadler, Michael B.
AU - Cazzaniga, Gianni
AU - Peters, Antoine H.F.M.
AU - Schwaller, Juerg
N1 - Publisher Copyright:
© 2018 the Author(s). Published by Wolters Kluwer Health, Inc.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
AB - 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.
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U2 - 10.1097/HS9.0000000000000051
DO - 10.1097/HS9.0000000000000051
M3 - Article
AN - SCOPUS:85061182614
SN - 2572-9241
VL - 2
JO - HemaSphere
JF - HemaSphere
IS - 4
M1 - e51
ER -
