High-affinity neurotrophin receptors and ligands promote leukemogenesis.
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.
Li
Zhixiong
Z
Department ofExperimental Hematology, Hannover Medical School, Hannover, Germany. li.zhixiong@mh-hannover.de
Beutel
Gernot
G
Rhein
Mathias
M
Meyer
Johann
J
Koenecke
Christian
C
Neumann
Thomas
T
Yang
Min
M
Krauter
Jürgen
J
von Neuhoff
Nils
N
Heuser
Michael
M
Diedrich
Helmut
H
Göhring
Gudrun
G
Wilkens
Ludwig
L
Schlegelberger
Brigitte
B
Ganser
Arnold
A
Baum
Christopher
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D020732:Cytogenetic Analysis; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D055815:Young Adult
D008024:Ligands; D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor