title: High-affinity neurotrophin receptors and ligands promote leukemogenesis.
abstract: 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.
authors.affiliation: Department ofExperimental Hematology, Hannover Medical School, Hannover, Germany. li.zhixiong@mh-hannover.de
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Li
authors.forename: Gernot
authors.initials: G
authors.lastname: Beutel
authors.forename: Mathias
authors.initials: M
authors.lastname: Rhein
authors.forename: Johann
authors.initials: J
authors.lastname: Meyer
authors.forename: Christian
authors.initials: C
authors.lastname: Koenecke
authors.forename: Thomas
authors.initials: T
authors.lastname: Neumann
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Nils
authors.initials: N
authors.lastname: von Neuhoff
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.forename: Helmut
authors.initials: H
authors.lastname: Diedrich
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wilkens
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Christopher
authors.initials: C
authors.lastname: Baum
mesh_terms: 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
chemical_list: D008024:Ligands; D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor