p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation (original) (raw)

• Letter
• Published: 23 October 2008
• Haoqiang Ying1 na1,
• Haiyan Yan1,
• Alec C. Kimmelman1,4,
• David J. Hiller8,
• An-Jou Chen1,
• Samuel R. Perry1,2,
• Giovanni Tonon1,
• Gerald C. Chu1,2,5,
• Zhihu Ding1,
• Jayne M. Stommel1,
• Katherine L. Dunn1,
• Ruprecht Wiedemeyer1,
• Mingjian J. You1,
• Cameron Brennan9,10,
• Y. Alan Wang1,2,
• Keith L. Ligon1,3,5,6,
• Wing H. Wong8,
• Lynda Chin1,2,7 &
• …
• Ronald A. DePinho1,2,11

Nature volume 455, pages 1129–1133 (2008)Cite this article

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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 events1,2,3. 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.

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Acknowledgements

We thank A. Berns for providing p53 L mice; S. Zhou and S. Jiang for mouse husbandry and care; R. T. Bronson for discussion on pathology analysis; K. Montgomery for discussion on sequencing; and Y.-H. Xiao, B. Feng and J. Zhang for bioinformatic help. H.Z. was supported by Helen Hay Whitney Foundation. H. Ying is a recipient of the Marsha Mae Moeslein Fellowship from the American Brain Tumor Association. A.C.K. is a recipient of the Leonard B. Holman Research Pathway Fellowship. Z.D. is supported by the Damon Runyon Cancer Research Foundation. J.M.S. is supported by a Ruth L. Kirschstein National Research Service Award Fellowship. R.W. is supported by a Mildred Scheel Fellowship (Deutsche Krebshilfe). Grant support comes from the Goldhirsh Foundation (R.A.D.), and NIH grants U01 CA84313 (R.A.D.), RO1CA99041 (L.C.) and 5P01CA95616 (R.A.D., L.C., W.H.W., C.B. and K.L.L.). R.A.D. is an American Cancer Society Research Professor supported by the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science.

Author Contributions H.Z. and H. Ying performed the experiments and contributed equally as first authors. R.A.D. supervised experiments and contributed as senior author. M.J.Y. generated the Pten L mouse allele. D.J.H., W.H.W. and G.T. conducted the microarray and promoter analyses. K.L.L., H.Z. and G.C.C. provided the pathology analyses. H. Yan, A.C.K., A.-J.C., S.R.P., Z.D., J.M.S, K.L.D. and R.W. performed the experiments. C.B. contributed patient samples and pathologic information. L.C. and Y.A.W. contributed to the writing of the manuscript.

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Author notes

1. Hongwu Zheng and Haoqiang Ying: These authors contributed equally to this work.

Authors and Affiliations

1. Department of Medical Oncology,,
   Hongwu Zheng, Haoqiang Ying, Haiyan Yan, Alec C. Kimmelman, An-Jou Chen, Samuel R. Perry, Giovanni Tonon, Gerald C. Chu, Zhihu Ding, Jayne M. Stommel, Katherine L. Dunn, Ruprecht Wiedemeyer, Mingjian J. You, Y. Alan Wang, Keith L. Ligon, Lynda Chin & Ronald A. DePinho
2. Center for Applied Cancer Science, Belfer Foundation Institute for Innovative Cancer Science,,
   Samuel R. Perry, Gerald C. Chu, Y. Alan Wang, Lynda Chin & Ronald A. DePinho
3. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA ,
   Keith L. Ligon
4. Harvard Radiation Oncology Program,,
   Alec C. Kimmelman
5. Department of Pathology,,
   Gerald C. Chu & Keith L. Ligon
6. Division of Neuropathology,,
   Keith L. Ligon
7. Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA,
   Lynda Chin
8. Department of Statistics, Stanford University, Stanford, California 94305, USA,
   David J. Hiller & Wing H. Wong
9. Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA,
   Cameron Brennan
10. Department of Neurosurgery, Weill-Cornell Medical College, New York, New York 10065, USA,
    Cameron Brennan
11. Departments of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA,
    Ronald A. DePinho

Authors

1. Hongwu Zheng
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2. Haoqiang Ying
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3. Haiyan Yan
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4. Alec C. Kimmelman
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5. David J. Hiller
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6. An-Jou Chen
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7. Samuel R. Perry
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8. Giovanni Tonon
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9. Gerald C. Chu
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10. Zhihu Ding
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11. Jayne M. Stommel
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12. Katherine L. Dunn
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13. Ruprecht Wiedemeyer
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14. Mingjian J. You
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15. Cameron Brennan
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16. Y. Alan Wang
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17. Keith L. Ligon
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18. Wing H. Wong
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19. Lynda Chin
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20. Ronald A. DePinho
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Correspondence toRonald A. DePinho.

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Zheng, H., Ying, H., Yan, H. et al. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation.Nature 455, 1129–1133 (2008). https://doi.org/10.1038/nature07443

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• Received: 02 May 2008
• Accepted: 10 September 2008
• Issue Date: 23 October 2008
• DOI: https://doi.org/10.1038/nature07443

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Editorial Summary

Glioblastoma: large-scale genomics and a lab model

The Cancer Genome Atlas, a large-scale genomics project to catalogue cancer-linked mutations, is starting to produce results. Glioblastoma, the most common brain cancer, was the first target for the project and the initial results, published AOP on 4 September, are now in print. Genes newly implicated in glioblastoma include tumour suppressors (NF1, RB1, ATM and APC) and several tyrosine kinase genes. Glioblastoma is extremely resistant to therapy, hence the potential importance of the development of a possible model system. Zheng et al. report that mice lacking the tumour suppressors p53 and Pten develop tumours resembling human glioblastomas, associated with increased Myc protein levels. As well as offering a potential system for testing therapeutics, this points to c-Myc as a possible drug target.