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Acute Leukemias

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

Leukemia volume 22, pages 66–77 (2008)Cite this article

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.

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Acknowledgements

We thank D Gary Gilliland and members of the Korsmeyer laboratory for helpful discussions and Elise Schindler for administrative assistance. Also, we thank the late Stanley J Korsmeyer, a tremendous mentor and friend, for his guidance throughout this work. This work was supported by NIH grants CA92551, the Charles H Hood Foundation, Friends of the Dana Farber Cancer Institute and the Leukemia Lymphoma Society (SAA).

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Author notes

  1. M C Stubbs and Y M Kim: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA

    M C Stubbs, Y M Kim, A V Krivtsov, Z Feng, J Agarwal, A L Kung & S A Armstrong

  2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, USA

    R D Wright, A L Kung & S A Armstrong

  3. Harvard Medical School, Boston, MA, USA

    A L Kung & S A Armstrong

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  1. M C Stubbs
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Correspondence to S A Armstrong.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Stubbs, M., Kim, Y., Krivtsov, A. et al. MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment. Leukemia 22, 66–77 (2008). https://doi.org/10.1038/sj.leu.2404951

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