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(American Journal of Pathology. 2003;163:321-331.)
© 2003 American Society for Investigative Pathology

MYCN Enhances P-gp/MDR1 Gene Expression in the Human Metastatic Neuroblastoma IGR-N-91 Model

Etienne Blanc*, David Goldschneider*, Eric Ferrandis{dagger}, Michel Barrois{dagger}, Gwenaëlle Le Roux*, Stéphane Leonce{ddagger}, Sétha Douc-Rasy*, Jean Bénard*{dagger} and Gilda Raguénez*

From the Centre National de la Recherche Scientifique,* Unité Mixte de Recherche (8126), Université Paris-Sud 11, Institut Fédératif de Recherche, and the Département de Biologie,{dagger} Service de Génétique, Institut Gustave-Roussy, Villejuif; and the Institut de Recherches Servier,{ddagger} Département de Biologie, Croissy sur Seine, France

Despite intensive high-dose chemotherapy and autologous hematopoietic stem cell transplantation, disseminated neuroblastoma (NB) frequently proves to be chemosensitive but not chemocurable, and more often so in NB-presenting MYCN amplification. To assess the direct relationship between the MYCN oncogene and chemoresistance acquisition during NB metastatic dissemination, we have studied MYCN and MDR1 genes using the human IGR-N-91 ectopic xenograft metastatic model. This characterized experimental in vitro model includes human neuroblasts derived from a subcutaneous primary tumor xenograft, disseminated blood cells, myocardium, and bone marrow (BM) metastatic cells. All IGR-N-91-derived neuroblasts harbor a consistent MYCN genomic content but, unlike primary tumor xenograft, BM, and myocardium, human neuroblasts elicit a concomitant increase in MYCN and MDR1 transcripts levels, consistent with chemoresistance phenotype and active P-gp. In contrast, no variation of MRP1 transcript level was associated with the metastatic process in this model. Using an MDR1 promoter-CAT construct, we have shown that the MycN protein activates MDR1 transcription both in exogenous transient MYCN-transfected SK-N-SH cells and in endogenous BM metastatic neuroblasts with an increase in the MYCN transcript level. Band-shift experiments indicate that IGR-N-91 cells enriched with the MycN transcription factor do bind to two E-box motifs localized within the MDR1 promoter. Overall, our data indicate that MYCN overexpression increment contributes to the acquired drug resistance that occurs throughout the NB metastatic process.




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