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Animal Models

Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease

Leukemia volume 21, pages 764–771 (2007)Cite this article

Abstract

Evidence is continuing to accumulate that the FMS-like tyrosine kinase 3 (FLT3) receptor plays an important role in acute leukemias. Acute myeloid leukemia patients often express constitutive active mutant forms of the receptor in their leukemic cells. A t(12;13)(p13;q12) translocation between Tel and the FLT3 receptor was recently described in a patient with myeloproliferative disease (MPD). Here a Tel-FLT3 construct mimicking this fusion protein was used to generate transgenic mice. The fusion protein was previously found to constitutively activate FLT3 signaling and transform Ba/F3 cells. Expression of the fusion protein in the transgenic mice was found in all tissues assayed including spleen, bone marrow (BM), thymus and liver. These mice developed splenomegaly and had a high incidence of MPD with extramedullary hematopoiesis in the liver and lymph nodes. Spleens also had increased dendritic and natural killer cell populations. In vitro analysis of the hematopoietic progenitor cells derived from Tel-FLT3 transgenic mice showed a significant increase in the number of CFU-GM in the BM, and CFU-GM, BFU-E and CFU-GEMM in the spleen. BM also showed significant increases of in vivo CFU-S colonies. Thus, transgenic mice expressing constitutively activated Tel-FLT3 develop MPD with a long latency and also result in the expansion of the hematopoietic stem/progenitor cells.

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Acknowledgements

We thank Larry Witte of the Imclone Systems for providing the FL. We also thank all members of the Small laboratory for valuable discussions. DS is also supported by the Kyle Haydock professorship in Oncology. This work was supported by grants frm the NCI (CA70970, CA90668 and CA91177: DS), Leukemia and Lymphoma Society (DS).

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  1. B R Baldwin and L Li: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    B R Baldwin, L Li, K-F Tse, S Small, M Collector, K A Whartenby, S J Sharkis, D Huso & D Small

  2. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    F Racke

  3. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    D Huso

  4. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    D Small

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Correspondence to D Small.

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Baldwin, B., Li, L., Tse, KF. et al. Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease. Leukemia 21, 764–771 (2007). https://doi.org/10.1038/sj.leu.2404532

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