title: MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment.
abstract: Human leukemias harboring chromosomal translocations involving the mixed lineage leukemia (MLL, HRX, ALL-1) gene possess high-level expression, and frequent activating mutations of the receptor tyrosine kinase FLT3. We used a murine bone marrow transplant model to assess cooperation between MLL translocation and FLT3 activation. We demonstrate that MLL-AF9 expression induces acute myelogenous leukemia (AML) in approximately 70 days, whereas the combination of MLL-AF9 and FLT3-ITD does so in less than 30 days. Secondary transplantation of splenic cells from diseased mice established that leukemia stem cells are present at a very high frequency of approximately 1:100 in both diseases. Importantly, prospectively isolated granulocyte macrophage progenitors (GMPs) coinfected with MLL-AF9 and FLT3-ITD give rise to a similar AML, with shorter latency than from GMP transduced with MLL-AF9 alone. Cooperation between MLL-AF9 and FLT3-ITD was further verified by real-time assessment of leukemogenesis using noninvasive bioluminescence imaging. We used this model to demonstrate that MLL-AF9/FLT3-ITD-induced leukemias are sensitive to FLT3 inhibition in a 2-3 week in vivo assay. These data show that activated FLT3 cooperates with MLL-AF9 to accelerate onset of an AML from whole bone marrow as well as a committed hematopoietic progenitor, and provide a new genetically defined model system that should prove useful for rapid assessment of potential therapeutics in vivo.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital, Boston, MA 02215, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Stubbs
authors.forename: Y M
authors.initials: YM
authors.lastname: Kim
authors.forename: A V
authors.initials: AV
authors.lastname: Krivtsov
authors.forename: R D
authors.initials: RD
authors.lastname: Wright
authors.forename: Z
authors.initials: Z
authors.lastname: Feng
authors.forename: J
authors.initials: J
authors.lastname: Agarwal
authors.forename: A L
authors.initials: AL
authors.lastname: Kung
authors.forename: S A
authors.initials: SA
authors.lastname: Armstrong
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D006098:Granulocytes / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D047468:Immunoprecipitation; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020080:Tandem Repeat Sequences; D014162:Transfection; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D008156:Luciferases; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3