MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment

Leukemia. 2008 Jan;22(1):66-77. doi: 10.1038/sj.leu.2404951. Epub 2007 Sep 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Southern
  • Blotting, Western
  • Bone Marrow Transplantation
  • Cell Proliferation
  • Disease Models, Animal*
  • Female
  • Granulocytes / cytology
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Immunophenotyping
  • Immunoprecipitation
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / pathology
  • Luciferases / metabolism
  • Macrophages / cytology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Promoter Regions, Genetic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tandem Repeat Sequences
  • Transfection
  • Tumor Cells, Cultured
  • fms-Like Tyrosine Kinase 3 / genetics*
  • fms-Like Tyrosine Kinase 3 / metabolism


  • MLL-AF9 fusion protein, human
  • Oncogene Proteins, Fusion
  • Myeloid-Lymphoid Leukemia Protein
  • Luciferases
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3