The most common form of malignant glioma in humans is termed """"""""primary glioblastoma"""""""". These tumors are characterized by amplified/mutated EGFR but are generally wild type with respect to P53 status. The genetic integrity of P53 in primary glioma is at odds with the aggressive growth of these tumors and their notorious resistance to radiation and cytotoxic drugs. In preliminary studies, we have found a potential resolution to this paradox. We show I) that essentially 100% of the CD133 positive stem cells that underlie malignant glioma in humans express the bHLH transcription represser OLIG2, ii) that OLIG2 suppresses expression of P21 - a key cell cycle inhibitor gene that is an inducible target gene of P53 and iii) that OLIG2 is essential for growth in a """"""""genetically relevant"""""""" murine model of primary glioma. The objective of our study plan is to test the hypothesis that OLIG2 sustains replication of primary glioma stem cells by opposing the action of P53 and suppressing the expression of P21. This hypothesis makes testable predications that we will address with a series of experiments to be conducted on fresh surgical isolates of malignant glioma. We will complement and validate the work on human tumor stem cells with experiments on murine models of glioma that emulate genetic lesions found in primary glioma and also secondary glioma (wild type EGFR but loss-of-function P53).
Specific aims are as follows:
Aim 1 is to test the prediction that the expression of P21 is precluded in CD133/OLIG2-positive stem cells of primary (P53 positive) gliomas.
Aim 2 is to test the prediction that suppression of OLIG2 will stimulate the expression of P21 in primary glioma stem cells and suppress the malignant phenotype.
Aim 3 is to test the prediction that P21 is epistatic to O/_/G2for maintenance of the malignant phenotype in stem cells for primary glioma.
Aim 4 is to test the prediction that other P53-inducible genes are also suppressed by OLIG2. These additional OLIG2 targets may account for the notorious resistance of primary gliomas to radiotherapy and chemotherapy. In the fullness of time, the work described may lead to new """"""""drugable targets"""""""" for the therapy of malignant glioma in humans. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057727-02
Application #
7465355
Study Section
Special Emphasis Panel (ZRG1-MDCN-N (02))
Program Officer
Fountain, Jane W
Project Start
2007-07-15
Project End
2011-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
2
Fiscal Year
2008
Total Cost
$427,500
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Zhou, Jing; Tien, An-Chi; Alberta, John A et al. (2017) A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2. Cell Rep 18:3167-3177
Meijer, Dimphna H; Sun, Yu; Liu, Tao et al. (2014) An amino terminal phosphorylation motif regulates intranuclear compartmentalization of Olig2 in neural progenitor cells. J Neurosci 34:8507-18
Silbereis, John C; Nobuta, Hiroko; Tsai, Hui-Hsin et al. (2014) Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain. Neuron 81:574-87
Meijer, Dimphna H; Kane, Michael F; Mehta, Shwetal et al. (2012) Separated at birth? The functional and molecular divergence of OLIG1 and OLIG2. Nat Rev Neurosci 13:819-31
Huillard, Emmanuelle; Hashizume, Rintaro; Phillips, Joanna J et al. (2012) Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. Proc Natl Acad Sci U S A 109:8710-5
Mehta, Shwetal; Huillard, Emmanuelle; Kesari, Santosh et al. (2011) The central nervous system-restricted transcription factor Olig2 opposes p53 responses to genotoxic damage in neural progenitors and malignant glioma. Cancer Cell 19:359-71
Sun, Yu; Meijer, Dimphna H; Alberta, John A et al. (2011) Phosphorylation state of Olig2 regulates proliferation of neural progenitors. Neuron 69:906-17
Stiles, Charles D; Rowitch, David H (2008) Glioma stem cells: a midterm exam. Neuron 58:832-46