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p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation

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

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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Figure 1: p53 and Pten inactivation cooperate to induce high-grade malignant gliomas.
Figure 2: hGFAP-Cre + ;p53 lox/lox ;Pten lox/+ gliomas mirror key features of human malignant gliomas.
Figure 3: p53 and Pten coordinately regulate Myc protein level as well as NSC self-renewal and differentiation.
Figure 4: Attenuated Myc expression restores hGFAP-Cre + ;p53 lox/lox ;Pten lox/+ TNS differentiation potential and reduces tumorigenic potential.

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Acknowledgements

We thank A. Berns for providing p53L 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 PtenL 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

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  1. Hongwu Zheng
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Correspondence to Ronald 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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