Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression.
IDH1mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutantIDH1(IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell-cycle arrest as well as a decreased ability to undergo neuronal differentiation.In vivo, Idh1-R132H expression reduced proliferation of cells within the germinal zone of the subventricular zone (SVZ). The NSCs within this area were dispersed and disorganized in mutant animals, suggesting that Idh1-R132H perturbed the NSCs and the microenvironment from which gliomas arise. In addition, tumor-bearing animals expressing mutant Idh1 displayed a prolonged survival and also overexpressed Olig2, features consistent with IDH1-mutated human gliomas. These data indicate that mutantIdh1disrupts the NSC microenvironment and the candidate cell-of-origin for glioma; thus, altering the progression of tumorigenesis. In addition, this study provides a mutantIdh1brain tumor model that genetically recapitulates human disease, laying the foundation for future investigations on mutantIDH1-mediated brain tumorigenesis and targeted therapy.Implications:Through the use of a conditional mutant mouse model that confers a less aggressive tumor phenotype, this study reveals that mutant Idh1 impacts the candidate cell-of-origin for gliomas.Mol Cancer Res; 15(5); 507-20. ©2017 AACR.
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Christopher J
CJ
Pirozzi
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Austin B
AB
Carpenter
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Matthew S
MS
Waitkus
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Catherine Y
CY
Wang
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Huishan
H
Zhu
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Landon J
LJ
Hansen
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Lee H
LH
Chen
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Paula K
PK
Greer
Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
Jie
J
Feng
Neurosurgery Department, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Yu
Y
Wang
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
Cheryl B
CB
Bock
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
Ping
P
Fan
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
Ivan
I
Spasojevic
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Roger E
RE
McLendon
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Darell D
DD
Bigner
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina. yiping.he@duke.edu hai.yan@duke.edu.
Yiping
Y
He
The Preston Robert Tisch Brain Tumor Center at Duke, Department of Pathology, Duke University Medical Center, Durham, North Carolina. yiping.he@duke.edu hai.yan@duke.edu.
Hai
H
Yan
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019175:DNA Methylation; D055879:Gene Knock-In Techniques; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D020547:Lateral Ventricles / Q000166:cytology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D058953:Neural Stem Cells / Q000166:cytology / Q000473:pathology; D000076104:Oligodendrocyte Transcription Factor 2 / Q000235:genetics; D011401:Promoter Regions, Genetic; D059016:Tumor Microenvironment
C512773:Olig2 protein, mouse; D000076104:Oligodendrocyte Transcription Factor 2; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human