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FLT3 and Malignant Transformation

Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation

Leukemia volume 14, pages 1766–1776 (2000)Cite this article

Abstract

Aberrant expression of FLT3 has been found in most cases of B-lineage ALL and AML, and subsets of T cell ALL, CML in blast crisis and CLL. In 20% of patients with AML the receptor has small internal tandem duplications of the juxtamembrane region which appear to contitutively activate the receptor. To investigate whether FLT3 activation could play a role in leukemia, we generated a constitutively activated FLT3 by fusing its cytoplasmic domain to the helix–loop–helix domain of TEL in analogy to the fusion that occurs with TEL-PDGFR in CMML. In vitrotranslation assays demonstrated oligomerization and intrinsic tyrosine kinase activity of the TEL-FLT3 chimeric receptor. Constitutively activated TEL-FLT3 conferred IL-3 independence and long-term proliferation to transfected Ba/F3 cells. Immunoblot analyses showed that JAK 2, STAT 3, STAT 5a, STAT 5b and CBL were tyrosine-phosphorylated in TEL-FLT3 expressing Ba/F3 cells in the absence of IL-3. These data suggest a possible role for the JAK/STAT pathway in FLT3 signaling. Transplantation of TEL-FLT3 expressing Ba/F3 cells into syngeneic mice caused mortality in all mice by 3 weeks after injection. Histopathologic analysis demonstrated a massive infiltration of mononuclear cells in the liver, spleen and bone marrow. The mimicking of naturally occurring TEL fusions provides an approach to assess aspects of the biology of activated FLT3, or other receptor-type tyrosine kinases (RTKs) in leukemic transformation.

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Acknowledgements

We gratefully acknowledge Enrico Novelli for technical assistance. We also thank Zemin Wang and Gerry Hoehn for helpful suggestions, and Linzhao Cheng and Joseph Ueland for critical review of the manuscript. This work was supported by a grant from the National Institute of Health (No. PO1CA70970).

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  1. Department of Oncology, John Hopkins University School of Medicine, Baltimore, MD, USA

    K-F Tse & D Small

  2. Department of Comparative Medicine, John Hopkins University School of Medicine, Baltimore, MD, USA

    G Mukherjee

  3. Department of Pediatrics, John Hopkins University School of Medicine, Baltimore, MD, USA

    D Small

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Tse, KF., Mukherjee, G. & Small, D. Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. Leukemia 14, 1766–1776 (2000). https://doi.org/10.1038/sj.leu.2401905

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