The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2

Abstract

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 identi®cation of genes with a role in neuroblastoma pathogenesis. Neuroblastoma also frequently show ampli®cation 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 identi®ed 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 con®rmed 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 upregulate nm23-H1 and nm23-H2 expression. Neuroblastoma tumor and cell line panels reveal a striking correlation between N-myc ampli®cation 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 ®ndings 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.

Prediction of clinical outcome and biological characterization of neuroblastoma by expression profiling

“…MYCN-amplification was concomitant with the overexpression of other genes mapping to chromosome 2p24-2p25, including ODC, NCYM and DDX1 (Figure 3a), confirming previous data (Godfried et al, 2002;Scott et al, 2003). This underscores the accuracy of patient assignment as well as the robustness of the data analysis.…”

NDPKA is not just a metastasis suppressor – be aware of its metastasis-promoting role in neuroblastoma

“…14 MYCN amplification is a frequent genetic alteration, occurring in~20% of patients with advanced neuroblastoma. 6 The ability of MYCN to upregulate nm23-H1 expression 17 can contribute to a high NDPK-A level in this subset of neuroblastomas. Intriguingly, neuroblastoma patients with MYCN amplification display a higher serum NDPK-A level than those without MYCN amplification.…”

Myc pathways provoking cell suicide and cancer

“…Myc target genes have been identified by a number of approaches, most recently in SAGE and microarray screens designed to capture those targets induced or repressed following conditional activation of the oncoprotein (Coller et al, 2000;Boon et al, 2001;Neiman et al, 2001;Schuldiner and Benvenisty, 2001;Godfried et al, 2002;Iritani et al, 2002;Menssen and Hermeking, 2002;Watson et al, 2002;Yu et al, 2002;Ellwood-Yen et al, 2003;Huang et al, 2003). The cast of targets is ponderous (with at least 647 targets already identified, see http://www.myc-cancer-gene.org).…”