Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis.
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 p16(INK4a) and p19(ARF), but not of p53, p16(INK4a), or p19(ARF), 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 p16(INK4a) and p19(ARF) 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.
Bachoo
Robert M
RM
Center for Neuro-Oncology, Boston, Massachusetts 02115, USA.
Maher
Elizabeth A
EA
Ligon
Keith L
KL
Sharpless
Norman E
NE
Chan
Suzanne S
SS
You
Mingjian James
MJ
Tang
Yi
Y
DeFrances
Jessica
J
Stover
Elizabeth
E
Weissleder
Ralph
R
Rowitch
David H
DH
Louis
David N
DN
DePinho
Ronald A
RA
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured / Q000166:cytology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D066246:ErbB Receptors / Q000502:physiology*; D049452:Green Fluorescent Proteins; D006720:Homozygote; D006801:Humans; D007124:Immunoenzyme Techniques; D015918:Infusion Pumps, Implantable; D008164:Luminescent Proteins / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000166:cytology*; D012190:Retroviridae / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014170:Transformation, Genetic / Q000502:physiology; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008164:Luminescent Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; D066246:ErbB Receptors