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  • Original Article
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Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice

Oncogene volume 36, pages 1516–1524 (2017)Cite this article

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Abstract

HOXA9, MEIS1 and FLT3 are genes frequently upregulated in human acute myeloid leukemia. Hoxa9 and Meis1 also cooperate to induce aggressive AML with high Flt3 expression in mice, suggesting an important role for Flt3 in Hoxa9/Meis1-induced leukemogenesis. To define the role of Flt3 in AML with high Hoxa9/Meis1, we treated mice with Hoxa9/Meis1-induced AML with the Flt3 inhibitor AC220, used an Flt3-ligand (FL−/−) knockout model, and investigated whether overexpression of Flt3 could induce leukemia together with overexpression of Hoxa9. Flt3 inhibition by AC220 did not delay AML development in mice transplanted with bone marrow cells overexpressing Hoxa9 and Meis1. In addition, Hoxa9/Meis1 cells induced AML in FL−/− mice as rapid as in wild-type mice. However, FL−/− mice had reduced organ infiltration compared with wild-type mice, suggesting some Flt3-dependent effect on leukemic invasiveness. Interestingly, leukemic Hoxa9/Meis1 cells from sick mice expressed high levels of Flt3 regardless of presence of its ligand, showing that Flt3 is a passive marker on these cells. In line with this, combined engineered overexpression of Flt3 and Hoxa9 did not accelerate the progression to AML. We conclude that the Hoxa9- and Meis1-associated upregulation of Flt3 is not a requirement for leukemic progression induced by Hoxa9 and Meis1.

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Acknowledgements

We wish to thank Carina Wasslavik, Christina Nilsson, and Susanne Li for valuable technical assistance. This work was supported by grants to LP from the Swedish Cancer Society (CAN2014/525) and the Västra Götalandsregionen (ALFGBG-431881). FK was supported by grants from Deutsche Krebshilfe grant 109420 (Max-Eder program), fellowship 2010/04 by the European Hematology Association, and by the Deutsche Forschungsgemeinschaft (SFB 1074, project A5). SYW was supported by a grant from Assar Gabrielsson’s foundation.

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Author notes

  1. L S Arabanian and S Y Wei: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden

    A Staffas, L S Arabanian, S Y Wei, S Ståhlman, P Johansson, L Fogelstrand & L Palmqvist

  2. Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden

    A Staffas, A Jansson, S Ståhlman, P Johansson, L Fogelstrand & L Palmqvist

  3. Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden

    S Y Wei

  4. Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

    J Cammenga

  5. Department of Hematology, Linköping University Hospital, Linköping, Sweden

    J Cammenga

  6. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    F Kuchenbauer

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  1. A Staffas
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Correspondence to L Palmqvist.

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Staffas, A., Arabanian, L., Wei, S. et al. Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice. Oncogene 36, 1516–1524 (2017). https://doi.org/10.1038/onc.2016.318

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  • DOI: https://doi.org/10.1038/onc.2016.318

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