TARGETED EXPRESSION OF MYCN CAUSES NEUROBLASTOMA IN TRANSGENIC MICE

The proto-oncogene MYCN is often amplified in human neuroblastomas. Th e assumption that the amplification contributes to tumorigenesis has n ever been tested directly. We have created transgenic mice that overex press MYCN in neuroectodermal cells and develop neuroblastoma, Analysi s of tumors by comparative genomic hybridization revealed gains and lo sses of at least seven chromosomal regions, all of which are syntenic with comparable abnormalities detected in human neuroblastomas. In add ition, we have shown that increases in MYCN dosage or deficiencies in either of the tumor suppressor genes NF1 or RB1 can augment tumorigene sis by the transgene, Our results provide direct evidence that MYCN ca n contribute to the genesis of neuroblastoma, suggest that the genetic events involved in the genesis of neuroblastoma can be tumorigenic in more than one chronological sequence, and offer a model for further s tudy of the pathogenesis and therapy of neuroblastoma.