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

Hongwu Zheng; Haoqiang Ying; Haiyan Yan; Alec C. Kimmelman; David J. Hiller; An Jou Chen; Samuel R. Perry; Giovanni Tonon; Gerald C. Chu; Zhihu Ding; Jayne M. Stommel; Katherine L. Dunn; Ruprecht Wiedemeyer; Mingjian J. You; Cameron Brennan; Y. Alan Wang; Keith L. Ligon; Wing H. Wong; Lynda Chin; Ronald A. DePinho

doi:10.1038/nature07443

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

Hongwu Zheng, Haoqiang Ying, Haiyan Yan, Alec C. Kimmelman, David J. Hiller, An Jou Chen, Samuel R. Perry, Giovanni Tonon, Gerald C. Chu, Zhihu Ding, Jayne M. Stommel, Katherine L. Dunn, Ruprecht Wiedemeyer, Mingjian J. You, Cameron Brennan, Y. Alan Wang, Keith L. Ligon, Wing H. Wong, Lynda Chin, Ronald A. DePinho

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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 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.

Original language	English (US)
Pages (from-to)	1129-1133
Number of pages	5
Journal	Nature
Volume	455
Issue number	7216
DOIs	https://doi.org/10.1038/nature07443
State	Published - Oct 23 2008
Externally published	Yes

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Zheng, H., Ying, H., Yan, H., Kimmelman, A. C., Hiller, D. J., Chen, A. J., Perry, S. R., Tonon, G., Chu, G. C., Ding, Z., Stommel, J. M., Dunn, K. L., Wiedemeyer, R., You, M. J., Brennan, C., Wang, Y. A., Ligon, K. L., Wong, W. H., Chin, L., & DePinho, R. A. (2008). p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature, 455(7216), 1129-1133. https://doi.org/10.1038/nature07443

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 2008, 'p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation', Nature, vol. 455, no. 7216, pp. 1129-1133. https://doi.org/10.1038/nature07443

@article{949e394ba81e422f8f3957452f1d68f5,

title = "p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation",

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.",

author = "Hongwu Zheng and Haoqiang Ying and Haiyan Yan and Kimmelman, {Alec C.} and Hiller, {David J.} and Chen, {An Jou} and Perry, {Samuel R.} and Giovanni Tonon and Chu, {Gerald C.} and Zhihu Ding and Stommel, {Jayne M.} and Dunn, {Katherine L.} and Ruprecht Wiedemeyer and You, {Mingjian J.} and Cameron Brennan and Wang, {Y. Alan} and Ligon, {Keith L.} and Wong, {Wing H.} and Lynda Chin and DePinho, {Ronald A.}",

note = "Funding Information: 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.",

year = "2008",

month = oct,

day = "23",

doi = "10.1038/nature07443",

language = "English (US)",

volume = "455",

pages = "1129--1133",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7216",

}

TY - JOUR

T1 - p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation

AU - Zheng, Hongwu

AU - Ying, Haoqiang

AU - Yan, Haiyan

AU - Kimmelman, Alec C.

AU - Hiller, David J.

AU - Chen, An Jou

AU - Perry, Samuel R.

AU - Tonon, Giovanni

AU - Chu, Gerald C.

AU - Ding, Zhihu

AU - Stommel, Jayne M.

AU - Dunn, Katherine L.

AU - Wiedemeyer, Ruprecht

AU - You, Mingjian J.

AU - Brennan, Cameron

AU - Wang, Y. Alan

AU - Ligon, Keith L.

AU - Wong, Wing H.

AU - Chin, Lynda

AU - DePinho, Ronald A.

N1 - Funding Information: 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.

PY - 2008/10/23

Y1 - 2008/10/23

N2 - 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.

AB - 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.

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ER -

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

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