The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2.
Gain of chromosome 17q material is the most frequent genetic abnormality in neuroblastomas. The common region of gain is at least 375 cR large, which has precluded the identification of genes with a role in neuroblastoma pathogenesis. Neuroblastoma also frequently show amplification of the N-myc oncogene, which correlates closely with 17q gain. Both events are strong predictors of unfavorable prognosis. To identify genes that are part of the N-myc downstream pathway, we constructed SAGE libraries of an N-myc transfected and a control cell line. This identified the chromosome 17q genes nm23-H1 and nm23-H2 as being 6-10 times induced in the N-myc expressing cells. Northern and Western blot analysis confirmed this up-regulation. Time-course experiment shows that both genes are induced within 4 h after N-myc is switched on. Furthermore, we demonstrate also that c-myc can up-regulate nm23-H1 and nm23-H2 expression. Neuroblastoma tumor and cell line panels reveal a striking correlation between N-myc amplification and mRNA and protein expression of both nm23 genes. We show that the nm23 genes are located at the edge of the common region of chromosome 17q gain previously described in neuroblastoma cell lines. Our findings suggest that nm23-H1 and nm23-H2 expression is increased by 17q gain in neuroblastoma and can be further up-regulated by myc overexpression. These observations suggest a major role for nm23-H1 and nm23-H2 in tumorigenesis of unfavorable neuroblastomas.
Godfried
Marc B
MB
Department of Human Genetics, Academic Medical Center, University of Amsterdam, PO box 22700, 1100 DE Amsterdam, The Netherlands.
Veenstra
Monique
M
v Sluis
Peter
P
Boon
Kathy
K
v Asperen
Ronald
R
Hermus
Marie Christien
MC
v Schaik
Barbara D C
BD
Voûte
Tom P A
TP
Schwab
Manfred
M
Versteeg
Rogier
R
Caron
Huib N
HN
D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D054778:NM23 Nucleoside Diphosphate Kinases; D009447:Neuroblastoma / Q000235:genetics*; D009701:Nucleoside-Diphosphate Kinase; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured
D054778:NM23 Nucleoside Diphosphate Kinases; D012333:RNA, Messenger; D014157:Transcription Factors; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; D020559:Monomeric GTP-Binding Proteins