Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma as a Preclinical Tool
Final rept. 1 Sep 2011-31 Aug 2014
DUKE UNIV DURHAM NC
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Diffuse Intrinsic Pontine Gliomas or DIPG, is a type of brain tumor that afflicts children and is the leading cause of death in pediatric brain tumor patients. One major obstacle to progress has been the lack of representative animal models that recapitulate the genetic alterations of the human disease in the appropriate cell-of-origin. Recent analysis of human DIPGs have unraveled the following key genetic alterations K27M H3.3 or H3.1 mutations in 80 of tumors, p53 mutations in 75 of tumors, and focal amplification of components of the RTKRasPI3K pathway in approximately 50 of tumors with 30 of tumors harboring amplification of PDGFR . Using the RCAStv-a system, we have previously reported the development of a DIPG model by overexpression of PDGF-B in nestin progenitors of Ink4a-ARF deficient mice. Here we report the development of several improved DIPG models by overexpression of PDGF-B and Cre in nestin progenitors of conditional p53 deficient mice, conditional PTEN mice, and combined conditional p53 and PTEN mice. In addition we have also generated a new DIPG model by overexpression of PDGF-B and Cre in GFAP progenitors of conditional p53 mice. Using expression profiling we note that they are genetically distinct. Lastly, to identify unique aspects of brainstem gliomagenesis we have compared the expression profile of the above described murine DIPG model to cortical gliomas induced by the same genetic alterations and unraveled that pax3 is a differentially expressed transcription factor that is upregulated in DIPGs and not in cortical gliomas.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research