Mutant IDH1 Promotes Glioma Formation In Vivo

被引：93

作者：

Philip, Beatrice ^{[1
,2
]}

Yu, Diana X. ^{[1
,2
]}

Silvis, Mark R. ^{[1
,2
]}

Shin, Clifford H. ^{[1
,3
]}

Robinson, James P. ^{[4
]}

Robinson, Gemma L. ^{[1
,2
]}

Welker, Adam E. ^{[1
]}

Angel, Stephanie N. ^{[1
,2
]}

Tripp, Sheryl R. ^{[5
]}

Sonnen, Joshua A. ^{[5
,6
]}

VanBrocklin, Matthew W. ^{[1
,2
,3
]}

Gibbons, Richard J. ^{[7
]}

Looper, Ryan E. ^{[8
]}

Colman, Howard ^{[1
,9
]}

Holmen, Sheri L. ^{[1
,2
,3
]}

机构：

[1] Univ Utah, Hlth Sci Ctr, Huntsman Canc Inst, Salt Lake City, UT 84112 USA

[2] Univ Utah, Hlth Sci Ctr, Dept Surg, Salt Lake City, UT 84112 USA

[3] Univ Utah, Hlth Sci Ctr, Dept Oncol Sci, Salt Lake City, UT 84112 USA

[4] Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA

[5] ARUP Inst Clin & Expt Pathol, Salt Lake City, UT 84108 USA

[6] Univ Utah, Hlth Sci Ctr, Dept Pathol, Salt Lake City, UT 84112 USA

[7] Univ Oxford, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford, England

[8] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA

[9] Univ Utah, Hlth Sci Ctr, Dept Neurosurg, Salt Lake City, UT 84112 USA

来源：

CELL REPORTS | 2018年 / 23卷 / 05期

关键词：

INTEGRATED GENOMIC ANALYSIS; ALPHA-KETOGLUTARATE; GLIOBLASTOMA; MUTATION; DIFFERENTIATION; CELLS; DNA; GLIOMAGENESIS; ACTIVATION; INHIBITOR;

D O I：

10.1016/j.celrep.2018.03.133

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II-III glioma and secondary glioblastoma (GBM). A causal role for IDH1(R132H) in gliomagenesis has been proposed, but functional validation in vivo has not been demonstrated. In this study, we assessed the role of IDH1(R132H) in glioma development in the context of clinically relevant cooperating genetic alterations in vitro and in vivo. Immortal astrocytes expressing IDH1(R132H) exhibited elevated (R)-2-hydroxyglutarate levels, reduced NADPH, increased proliferation, and anchorage-independent growth. Although not sufficient on its own, IDH1(R132H) cooperated with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo. These tumors resembled proneural human mutant IDH1 GBM genetically, histologically, and functionally. Our findings support the hypothesis that IDH1(R132H) promotes glioma development. This model enhances our understanding of the biology of IDH1(R132H)-driven gliomas and facilitates testing of therapeutic strategies designed to combat this deadly disease.

引用

页码：1553 / 1564

页数：12

共 43 条

[1]

Almeida Jonas S, 2012, J Pathol Inform, V3, P25, DOI 10.4103/2153-3539.98813

[2] Mutant IDH1 regulates the tumor-associated immune system in gliomas [J].

Amankulor, Nduka M. ;

Kim, Youngmi ;

Arora, Sonali ;

Kargl, Julia ;

Szulzewsky, Frank ;

Hanke, Mark ;

Margineantu, Daciana H. ;

Rao, Aparna ;

Bolouri, Hamid ;

Delrow, Jeff ;

Hockenbery, David ;

Houghton, A. McGarry ;

Holland, Eric C. .

GENES & DEVELOPMENT, 2017, 31 (08) :774-786

[3] Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis [J].

Bardella, Chiara ;

Al-Dalahmah, Osama ;

Krell, Daniel ;

Brazauskas, Pijus ;

Al-Qahtani, Khalid ;

Tomkova, Marketa ;

Adam, Julie ;

Serres, Sebastien ;

Lockstone, Helen ;

Freeman-Mills, Luke ;

Pfeffer, Inga ;

Sibson, Nicola ;

Goldin, Robert ;

Schuster-Boeckler, Benjamin ;

Pollard, Patrick J. ;

Soga, Tomoyoshi ;

McCullagh, James S. ;

Schofield, Christopher J. ;

Mulholland, Paul ;

Ansorge, Olaf ;

Kriaucionis, Skirmantas ;

Ratcliffe, Peter J. ;

Szele, Francis G. ;

Tomlinson, Ian .

CANCER CELL, 2016, 30 (04) :578-594

[4] Properties and regulation of glutamine transporter SN1 by protein kinases SGK and PKB [J].

Boehmer, C ;

Okur, F ;

Setiawan, I ;

Bröer, S ;

Lang, F .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2003, 306 (01) :156-162

[5] Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas [J].

Brat, Daniel J. ;

Verhaak, Roel G. W. ;

Al-dape, Kenneth D. ;

Yung, W. K. Alfred ;

Salama, Sofie R. ;

Cooper, Lee A. D. ;

Rheinbay, Esther ;

Miller, C. Ryan ;

Vitucci, Mark ;

Morozova, Olena ;

Robertson, A. Gordon ;

Noushmehr, Houtan ;

Laird, Peter W. ;

Cherniack, Andrew D. ;

Akbani, Rehan ;

Huse, Jason T. ;

Ciriello, Giovanni ;

Poisson, Laila M. ;

Barnholtz-Sloan, Jill S. ;

Berger, Mitchel S. ;

Brennan, Cameron ;

Colen, Rivka R. ;

Colman, Howard ;

Flanders, Adam E. ;

Giannini, Caterina ;

Grifford, Mia ;

Iavarone, Antonio ;

Jain, Rajan ;

Joseph, Isaac ;

Kim, Jaegil ;

Kasaian, Katayoon ;

Mikkelsen, Tom ;

Murray, Bradley A. ;

O'Neill, Brian Patrick ;

Pachter, Lior ;

Parsons, Donald W. ;

Sougnez, Carrie ;

Sulman, Erik P. ;

Vandenberg, Scott R. ;

Van Meir, Erwin G. ;

von Deimling, Andreas ;

Zhang, Hailei ;

Crain, Daniel ;

Lau, Kevin ;

Mallery, David ;

Morris, Scott ;

Paulauskis, Joseph ;

Penny, Robert ;

Shelton, Troy ;

Sherman, Mark .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 372 (26) :2481-2498

[6] Benefit From Procarbazine, Lomustine, and Vincristine in Oligodendroglial Tumors Is Associated With Mutation of IDH [J].

Cairncross, J. Gregory ;

Wang, Meihua ;

Jenkins, Robert B. ;

Shaw, Edward G. ;

Giannini, Caterina ;

Brachman, David G. ;

Buckner, Jan C. ;

Fink, Karen L. ;

Souhami, Luis ;

Laperriere, Normand J. ;

Huse, Jason T. ;

Mehta, Minesh P. ;

Curran, Walter J., Jr. .

JOURNAL OF CLINICAL ONCOLOGY, 2014, 32 (08) :783-+

[7] Multidimensional scaling of diffuse gliomas: application to the 2016 World Health Organization classification system with prognostically relevant molecular subtype discovery [J].

Cimino, Patrick J. ;

Zager, Michael ;

McFerrin, Lisa ;

Wirsching, Hans-Georg ;

Bolouri, Hamid ;

Hentschel, Bettina ;

von Deimling, Andreas ;

Jones, David ;

Reifenberger, Guido ;

Weller, Michael ;

Holland, Eric C. .

ACTA NEUROPATHOLOGICA COMMUNICATIONS, 2017, 5 :39

[8] DNA copy number analysis of Grade II-III and Grade IV gliomas reveals differences in molecular ontogeny including chromothripsis associated with IDH mutation status [J].

Cohen, Adam ;

Sato, Mariko ;

Aldape, Kenneth ;

Mason, Clinton C. ;

Alfaro-Munoz, Kristin ;

Heathcock, Lindsey ;

South, Sarah T. ;

Abegglen, Lisa M. ;

Schiffman, Joshua D. ;

Colman, Howard .

ACTA NEUROPATHOLOGICA COMMUNICATIONS, 2015, 3 :34

[9] IDH1 and IDH2 Mutations in Gliomas [J].

Cohen, Adam L. ;

Holmen, Sheri L. ;

Colman, Howard .

CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS, 2013, 13 (05)

[10] IDH mutations in cancer and progress toward development of targeted therapeutics [J].

Dang, L. ;

Yen, K. ;

Attar, E. C. .

ANNALS OF ONCOLOGY, 2016, 27 (04) :599-608

← 1 2 3 4 5 →