A constitutively active epidermal growth factor receptor cooperates with disruption of G(1) cell-cycle arrest pathways to induce glioma-like lesions in mice

The epidermal growth factor receptor (EGFR) gene is amplified or mutated in 30%-50% of human gliobastoma multiforme (GBM). These mutations are associa ted usually with deletions of the INK4a-ARF locus, which encodes two gene p roducts (p16(INK4a) and p19(ARF)) involved in cell-cycle arrest and apoptos is. We have investigated the role of EGFR mutation in gliomagenesis, using avian retroviral vectors to transfer a mutant EGER gene to glial precursors and astrocytes in transgenic mice expressing tv-a, a gene encoding the ret rovirus receptor. TVA, under control of brain cell type-specific promoters. We demonstrate that expression of a constitutively active, mutant form of EGER in cells in the glial lineage can induce lesions with many similaritie s to human gliomas. These lesions occur more frequently with gene transfer to mice expressing tv-a from the progenitor-specific nestin promoter than t o mice expressing tv-a from the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, suggesting that tumors arise more efficiently from immature cells in the glial lineage. Furthermore, EGFR-induced gliomagenes is appears to require additional mutations in genes encoding proteins invol ved in cell-cycle arrest pathways. We have produced these combinations by s imultaneously infecting tv-a transgenic mice with vectors carrying cdk4 and EGFR or by infecting tv-a transgenic mice bearing a disrupted INK4a-ARF lo cus with the EGFR-carrying vector alone. Moreover, EGFR-induced gliomagenes is does not occur in conjunction with p53 deficiency, unless the mice are a lso infected with a vector carrying cdk4. The gliomagenic combinations of g enetic lesions required in mice are similar to those found in human gliomas .