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 Blood, 26 February 2009, Vol. 113, No. 9, pp. 2028-2037.
Prepublished online as a Blood First Edition Paper on December 4, 2008; DOI 10.1182/blood-2008-05-155200.

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MYELOID NEOPLASIA

High-affinity neurotrophin receptors and ligands promote leukemogenesis

Zhixiong Li1,*, Gernot Beutel2,*, Mathias Rhein1,*, Johann Meyer1, Christian Koenecke2, Thomas Neumann1, Min Yang1, Jürgen Krauter2, Nils von Neuhoff3, Michael Heuser2, Helmut Diedrich2, Gudrun Göhring3, Ludwig Wilkens3, Brigitte Schlegelberger3, Arnold Ganser2, and Christopher Baum1,4

Departments of1 Experimental Hematology and 2 Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, and 3 Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany; and 4 Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, OH

Neurotrophins (NTs) and their receptors play a key role in neurogenesis and survival. The TRK (tropomyosin-related kinase) receptor protein tyrosine kinases (TRKA, TRKB, TRKC) are high-affinity NT receptors that are expressed in a variety of human tissues. Their role in normal and malignant hematopoiesis is poorly understood. In a prospective study involving 94 adult patients we demonstrate for the first time cell-surface expression of the 3 TRKs and constitutive activation in blasts from patients with de novo or secondary acute leukemia. At least one TRK was expressed in 55% of the analyzed cases. We establish a clear correlation between the TRK expression pattern and FAB classification. Although only few point mutations were found in TRK sequences by reverse-transcriptase–polymerase chain reaction (RT-PCR), we observed coexpression of BDNF (ligand for TRKB) in more than 50% of TRKB+ cases (16/30). Activation of TRKA or TRKB by NGF and BDNF, respectively, efficiently rescued murine myeloid cells from irradiation-induced apoptosis. Coexpression of TRKB/BDNF or TRKA/NGF in murine hematopoietic cells induced leukemia. Moreover, activation of TRKs was important for survival of both human and murine leukemic cells. Our findings suggest that TRKs play an important role in leukemogenesis and may serve as a new drug target.


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