Author/Authors :
P. Bachoo، نويسنده , , Robert M and Maher، نويسنده , , Elizabeth A and Ligon، نويسنده , , Keith L and Sharpless، نويسنده , , Norman E and Chan، نويسنده , , Suzanne S and You، نويسنده , , Mingjian James and Tang، نويسنده , , Yi and DeFrances، نويسنده , , Jessica and Stover، نويسنده , , Elizabeth and Weissleder، نويسنده , , Ralph and Rowitch، نويسنده , , David H and Louis، نويسنده , , David N and DePinho، نويسنده , , Ronald A، نويسنده ,
Abstract :
Ink4a/Arf inactivation and epidermal growth factor receptor (EGFR) activation are signature lesions in high-grade gliomas. How these mutations mediate the biological features of these tumors is poorly understood. Here, we demonstrate that combined loss of p16INK4a and p19ARF, but not of p53, p16INK4a, or p19ARF, enables astrocyte dedifferentiation in response to EGFR activation. Moreover, transduction of Ink4a/Arf−/− neural stem cells (NSCs) or astrocytes with constitutively active EGFR induces a common high-grade glioma phenotype. These findings identify NSCs and astrocytes as equally permissive compartments for gliomagenesis and provide evidence that p16INK4a and p19ARF synergize to maintain terminal astrocyte differentiation. These data support the view that dysregulation of specific genetic pathways, rather than cell-of-origin, dictates the emergence and phenotype of high-grade gliomas.
