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Title:Increased mitochondrial activity in a novel IDH1-R132H mutant human oligodendroglioma xenograft model : in situ detection of 2-HG and [alpha]-KG
Authors:ID Navis, Anna C. (Author)
ID Niclou, Simone P. (Author)
ID Fack, Fred (Author)
ID Stieber, Daniel (Author)
ID Lith, Sanne A. M. van (Author)
ID Verrijp, Kiek (Author)
ID Wright, Alan F. (Author)
ID Stauber, Jonathan (Author)
ID Tops, Bastiaan (Author)
ID Otte-Holler, Irene (Author)
ID Wevers, Ron A. (Author)
ID Rooij, Arno van (Author)
ID Pusch, Stefan (Author)
ID Deimling, Andreas von (Author)
ID Tigchelaar, Wikky (Author)
ID Noorden, Cornelis J. F. van (Author)
ID Wesseling, Pieter (Author)
ID Leenders, William P. J. (Author)
Files:URL URL - Source URL, visit https://doi.org/10.1186/2051-5960-1-18
 
.pdf PDF - Presentation file, download (1,76 MB)
MD5: DD7DE412BB3AF3306FA8C35B5B862A13
 
Language:English
Typology:1.01 - Original Scientific Article
Organization:Logo NIB - National Institute of Biology
Abstract:Background Point mutations in genes encoding NADP+-dependent isocitrate dehydrogenases (especially IDH1) are common in lower grade diffuse gliomas and secondary glioblastomas and occur early during tumor development. The contribution of these mutations to gliomagenesis is not completely understood and research is hampered by the lack of relevant tumor models. We previously described the development of the patient-derived high-grade oligodendroglioma xenograft model E478 that carries the commonly occurring IDH1-R132H mutation. We here report on the analyses of E478 xenografts at the genetic, histologic and metabolic level. Results LC-MS and in situ mass spectrometric imaging by LESA-nano ESI-FTICR revealed high levels of the proposed oncometabolite D-2-hydroxyglutarate (D-2HG), the product of enzymatic conversion of α-ketoglutarate (α-KG) by IDH1-R132H, in the tumor but not in surrounding brain parenchyma. α-KG levels and total NADP+-dependent IDH activity were similar in IDH1-mutant and -wildtype xenografts, demonstrating that IDH1-mutated cancer cells maintain α-KG levels. Interestingly, IDH1-mutant tumor cells in vivo present with high densities of mitochondria and increased levels of mitochondrial activity as compared to IDH1-wildtype xenografts. It is not yet clear whether this altered mitochondrial activity is a driver or a consequence of tumorigenesis. Conclusions The oligodendroglioma model presented here is a valuable model for further functional elucidation of the effects of IDH1 mutations on tumor metabolism and may aid in the rational development of novel therapeutic strategies for the large subgroup of gliomas carrying IDH1 mutations.
Keywords:gliomaI, IDH mutations, xenograft, D-2-hydroxyglutarate, [alpha]-ketoglutarate, mitochondria: LESA-nano ESI-FTIC
Publication status:Published
Publication version:Version of Record
Publication date:29.05.2013
Year of publishing:2013
Number of pages:str. 1-12
Numbering:Vol. 1
PID:20.500.12556/DiRROS-20026 New window
UDC:577.2
ISSN on article:2051-5960
DOI:10.1186/2051-5960-1-18 New window
COBISS.SI-ID:4651599 New window
Note:Nasl. z nasl. zaslona; Opis vira z dne 19. 3. 2018;
Publication date in DiRROS:02.08.2024
Views:472
Downloads:316
Metadata:XML DC-XML DC-RDF
:
NAVIS, Anna C., NICLOU, Simone P., FACK, Fred, STIEBER, Daniel, LITH, Sanne A. M. van, VERRIJP, Kiek, WRIGHT, Alan F., STAUBER, Jonathan, TOPS, Bastiaan, OTTE-HOLLER, Irene, WEVERS, Ron A., ROOIJ, Arno van, PUSCH, Stefan, DEIMLING, Andreas von, TIGCHELAAR, Wikky, NOORDEN, Cornelis J. F. van, WESSELING, Pieter and LEENDERS, William P. J., 2013, Increased mitochondrial activity in a novel IDH1-R132H mutant human oligodendroglioma xenograft model : in situ detection of 2-HG and [alpha]-KG. Acta neuropathologica communications [online]. 2013. Vol. 1, p. 1–12. [Accessed 9 April 2025]. DOI 10.1186/2051-5960-1-18. Retrieved from: https://dirros.openscience.si/IzpisGradiva.php?lang=eng&id=20026
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Record is a part of a journal

Title:Acta neuropathologica communications
Shortened title:Acta Neuropathol. Commun.
Publisher:BioMed Central
ISSN:2051-5960
COBISS.SI-ID:522939929 New window

Document is financed by a project

Funder:Other - Other funder or multiple funders
Project number:2010(1)- 01
Name:the Hersenstichting
Funder:Other - Other funder or multiple funders
Funding programme:FNR in Luxembourg
Project number:C10/BM/784322
Name:ESCAPE
Acronym:CORE
Funder:Other - Other funder or multiple funders
Acronym:RUNMC

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License:CC BY 2.0, Creative Commons Attribution 2.0 Generic
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