Loss of a FYN-regulated differentiation and growth arrest pathway in advanced stage neuroblastoma.
Tumor stage, age of patient, and amplification of MYCN predict disease outcome in neuroblastoma. To gain insight into the underlying molecular pathways, we have obtained expression profiles from 94 primary neuroblastoma specimens. Advanced tumor stages show a characteristic expression profile that includes downregulation of multiple genes involved in signal transduction through Fyn and the actin cytoskeleton. High expression of Fyn and high Fyn kinase activity are restricted to low-stage tumors. In culture, expression of active Fyn kinase induces differentiation and growth arrest of neuroblastoma cells. Expression of Fyn predicts long-term survival independently of MYCN amplification. Amplification of MYCN correlates with deregulation of a distinct set of genes, many of which are target genes of Myc. Our data demonstrate a causal role for Fyn kinase in the genesis of neuroblastoma.
Berwanger
Bernd
B
Institute for Molecular Biology and Tumor Research, Emil-Mannkopff-Strasse 2, 35037 Marburg, Germany.
Hartmann
Oliver
O
Bergmann
Eckhard
E
Bernard
Sandra
S
Nielsen
Dirk
D
Krause
Michael
M
Kartal
Ali
A
Flynn
Daniel
D
Wiedemeyer
Ruprecht
R
Schwab
Manfred
M
Schäfer
Helmut
H
Christiansen
Holger
H
Eilers
Martin
M
D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D018572:Disease-Free Survival; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D007223:Infant; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn