1. ¹Department of Experimental Hematology, Hannover Medical School, Hannover, Germany
2. ²Department of Hematology, Hemostaseology and Oncology, Hannover Medical School, Hannover, Germany
3. ³Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany
4. ⁴Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
5. ⁵H Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
6. ⁶Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

Correspondence: Dr Z Li, Department of Experimental Hematology, OE6960, Hannover Medical School, Carl-Neuberg-Strae 1, 30625 Hannover, Germany. E-mail: li.zhixiong@mh-hannover.de

⁷These authors contributed equally to this work.

Received 16 February 2007; Revised 1 July 2007; Accepted 2 July 2007; Published online 2 August 2007.

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 TrkA, a mutant of TRKA (tropomyosin-related kinase A) isolated from a patient with acute myeloid leukemia (AML). Retroviral expression of TrkA in myeloid 32D cells induced AML in syngeneic C3H/Hej mice (n=11/11, latency 4 weeks). C57Bl/6J mice transplanted with TrkA-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.