Human Gene Set: ZHENG_GLIOBLASTOMA_PLASTICITY_UP

For the Mouse gene set with the same name, see ZHENG_GLIOBLASTOMA_PLASTICITY_UP

Standard name ZHENG_GLIOBLASTOMA_PLASTICITY_UP
Systematic name M1796
Brief description The glioblastoma multiforme (GBM) plasticity signature: genes up-regulated in neural stem cells (NSC) with double knockout of TP53 and PTEN [GeneID=7157;5728] vs those with knockout of TP53 alone.
Full description or abstract Glioblastoma (GBM) is a highly lethal brain tumour presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as a high-grade disease that typically harbours mutations in EGFR, PTEN and INK4A/ARF (also known as CDKN2A), and the secondary GBM subtype evolves from the slow progression of a low-grade disease that classically possesses PDGF and TP53 events. Here we show that concomitant central nervous system (CNS)-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with notable clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted TP53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as the expected PTEN mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives increased Myc protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of NSCs doubly null for p53 and Pten (p53(-/-) Pten(-/-)) as well as tumour neurospheres (TNSs) derived from this model. Myc also serves to maintain robust tumorigenic potential of p53(-/-) Pten(-/-) TNSs. These murine modelling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumour suppressor mutation profile in human primary GBM and establish Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 18948956   Authors: Zheng H,Ying H,Yan H,Kimmelman AC,Hiller DJ,Chen AJ,Perry SR,Tonon G,Chu GC,Ding Z,Stommel JM,Dunn KL,Wiedemeyer R,You MJ,Brennan C,Wang YA,Ligon KL,Wong WH,Chin L,DePinho RA
Exact source Table 2S
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Source species Mus musculus
Contributed by Jessica Robertson (MSigDB Team)
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identifier namespace		 Mouse_RefSeq
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Version history 3.1: First introduced

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