title: Differential requirement for wild-type Flt3 in leukemia initiation among mouse models of human leukemia.
abstract: FLT3 is one of the most frequently mutated genes in acute leukemias. However, the role in leukemogenesis of wild-type (wt) FLT3, which is highly expressed in many hematologic malignancies, is unclear. We show here that in mouse models established by retroviral transduction of leukemic fusion proteins, deletion of Flt3 strongly inhibits MLL-ENL and to lesser extent p210(BCR-ABL)-induced leukemogenesis, but has no effect in MLL-AF9 or AML1-ETO9a models. Flt3 acts at the level of leukemic stem cells (LSCs), as a fraction of LSCs in MLL-ENL, but not in MLL-AF9-induced leukemia, expressed Flt3 in vivo, and Flt3 expression on LSCs was associated with leukemia development in this model. Furthermore, efficiency of MLL-ENL, but not of MLL-AF9-induced leukemia induction was significantly enhanced after transduction of Flt3(+) compared to Flt3(-) wt myeloid progenitors. However, Flt3 is not required for immortalization of bone marrow cells in vitro by MLL-ENL and does not affect colony formation by MLL-ENL LSCs in vitro, suggesting that in vitro models do not reflect the in vivo biology of MLL-ENL leukemia with respect to Flt3 requirement. We conclude that wt Flt3 plays a role in leukemia initiation in vivo, which is, however, not universal.
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kamezaki
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Larry L
authors.initials: LL
authors.lastname: Luchsinger
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA. Electronic address: hs2680@columbia.edu.
authors.forename: Hans-Willem
authors.initials: HW
authors.lastname: Snoeck
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D015514:Oncogene Proteins, Fusion; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3