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Animal Models

Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, ΔTrkA

Leukemia volume 21, pages 2171–2180 (2007)Cite this article

Abstract

Neurotrophins and their receptors play a key role in neurogenesis and survival. However, we and others have recently obtained evidence for a potential involvement of this receptor system in leukemia. To investigate mechanisms underlying the leukemogenic potential of activated neurotrophin receptor signaling, we analyzed in vivo leukemogenesis mediated by ΔTrkA, a mutant of TRKA (tropomyosin-related kinase A) isolated from a patient with acute myeloid leukemia (AML). Retroviral expression of ΔTrkA in myeloid 32D cells induced AML in syngeneic C3H/Hej mice (n=11/11, latency ∼4 weeks). C57Bl/6J mice transplanted with ΔTrkA-transduced primary lineage negative (Lin−) bone marrow cells died of a transient polyclonal AML (n=7/15, latency of <12 days). Serial transplantation of AML cells did not re-induce this disease but rather acute lymphoblastic leukemia (ALL, latency >78 days). All primary recipients surviving the early AML developed clonal ALL or myeloid leukemia (latency >72 days) that required additional genetic lesions. PI3K and mTOR-raptor were identified as the crucial mediators of leukemic transformation, whereas STAT and MAP kinase signaling pathways were not activated. Thus, our findings reveal potent and unique transforming properties of altered neurotrophin receptor signaling in leukemogenesis, and encourage further analyses of neurotrophin receptors and downstream signaling events in hematological malignancies.

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Acknowledgements

This study was supported by the Deutsche Krebshilfe (grant: 10-2090-Li I) and DFG excellence cluster REBIRTH. CB is also supported by the National Cancer Institute (R01-CA107492-01A2). MR is a student of the MD/PhD program in Hannover Medical School, supported by the Deutsche José Carreras Leukämie-Stiftung (grant: DJCLS F05/10). BF's group was supported by the DFG (FE568/5-2). GWR was supported by the National Cancer Institute (K01CA098330) and the V Foundation for Cancer Research. We are very grateful to Maimona Id, Nicole Brauer-Dewor and Dung Ludwig for technical assistance, Daniel Wicke and Viktor Grünwald for providing 32D MPL cells and antibodies against S6 protein, and Rolf Baumann, Hans Grundtke, Jörg Frühauf and Bernd Polivka (Radiotherapy, Hannover Medical School) for irradiation of animals.

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  1. J Meyer and M Rhein: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Hematology, Hannover Medical School, Hannover, Germany

    J Meyer, M Rhein, B Schiedlmeier, O Kustikova, T Neumann, M Yang, C Baum & Z Li

  2. Department of Hematology, Hemostaseology and Oncology, Hannover Medical School, Hannover, Germany

    J Meyer, M Rhein, B Schiedlmeier, O Kustikova, T Neumann, M Yang, A Ganser, C Baum & Z Li

  3. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    C Rudolph, K Kamino & B Schlegelberger

  4. Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    A Wahlers & B Fehse

  5. H Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA

    G W Reuther

  6. Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    C Baum

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Correspondence to Z Li.

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

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Meyer, J., Rhein, M., Schiedlmeier, B. et al. Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, ΔTrkA. Leukemia 21, 2171–2180 (2007). https://doi.org/10.1038/sj.leu.2404882

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