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FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model

Oncogene volume 24, pages 7882–7892 (2005)Cite this article

Abstract

Activating FMS-like tyrosine kinase 3 (FLT3) mutations have been identified in ∼30% of patients with acute myelogenous leukemia (AML), and recently in a smaller subset of patients with acute lymphoblastic leukemia (ALL). To explore the in vivo consequences of an activating FLT3 internal tandem duplication mutation (FLT3-ITD), we created a transgenic mouse model in which FLT3-ITD was expressed under the control of the vav hematopoietic promoter. Five independent lines of vav-FLT3-ITD transgenic mice developed a myeloproliferative disease with high penetrance and a disease latency of 6–12 months. The phenotype was characterized by splenomegaly, megakaryocytic hyperplasia, and marked thrombocythemia, but without leukocytosis, polycythemia, or marrow fibrosis, displaying features reminiscent of the human disease essential thrombocythemia (ET). Clonal immature B- or T-lymphoid disease was observed in two additional founder mice, respectively, that could be secondarily transplanted to recipient mice that rapidly developed lymphoid disease. Treatment of these mice with the FLT3 tyrosine kinase inhibitor, PKC412, resulted in suppression of disease and a statistically significant prolongation of survival. These results demonstrate that FLT3-ITD is capable of inducing myeloproliferative as well as lymphoid disease, and indicate that small-molecule tyrosine kinase inhibitors may be an effective treatment for lymphoid malignancies in humans that are associated with activating mutations in FLT3.

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Acknowledgements

We thank members of the Gilliland laboratory for valuable advice and discussions. This work was supported in part by NIH grants CA66996 and DK50654, and by a Leukemia and Lymphoma Society SCOR grant. BHL is a recipient of a Physician-Scientist Fellowship from the Leukemia Research Foundation and was previously supported by NIH departmental training grant 5T32HL 07627-16, and DGG is an Investigator in the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, 02115, MA, USA

    Benjamin H Lee, Ema Anastasiadou, Christina L Boulton, Sarah W Joseph, Sonia M Amaral, David P Curley, Nicole Duclos, Brian J P Huntly & Dwight Gary Gilliland

  2. Department of Pathology, Brigham and Women's Hospital, Boston, 02115, MA, USA

    Benjamin H Lee

  3. Department of Pathology, Emory University, Atlanta, 30322, GA, USA

    Ifor R Williams

  4. Novartis Pharma AG, Basel, Switzerland

    Doriano Fabbro

  5. Dana Farber Cancer Institute, Harvard Medical School, Boston, 02115, MA, USA

    James D Griffin

  6. Howard Hughes Medical Institute, Harvard Medical School, Boston, 02115, MA, USA

    Dwight Gary Gilliland

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  1. Benjamin H Lee
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Correspondence to Dwight Gary Gilliland.

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Lee, B., Williams, I., Anastasiadou, E. et al. FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model. Oncogene 24, 7882–7892 (2005). https://doi.org/10.1038/sj.onc.1208933

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