Characterization of iPSCs derived from low grade gliomas revealed early regional chromosomal amplifications during gliomagenesis

Zhong Liu, Pulin Che, Juan J. Mercado, James R. Hackney, Gregory K. Friedman, Cheng Zhang, Zhiying You, Xinyang Zhao, Qiang Ding, Kitai Kim, Hu Li, Xiaoguang Liu, James M. Markert, Burt Nabors, G. Yancey Gillespie, Rui Zhao, Xiaosi Han

Research output: Contribution to journalArticle

Abstract

Introduction: IDH1 mutation has been identified as an early genetic event driving low grade gliomas (LGGs) and it has been proven to exerts a powerful epigenetic effect. Cells containing IDH1 mutation are refractory to epigenetical reprogramming to iPSC induced by expression of Yamanaka transcription factors, a feature that we employed to study early genetic amplifications or deletions in gliomagenesis. Methods: We made iPSC clones from freshly surgically resected IDH1 mutant LGGs by forced expression of Yamanaka transcription factors. We sequenced the IDH locus and analyzed the genetic composition of multiple iPSC clones by array-based comparative genomic hybridization (aCGH). Results: We hypothesize that the primary cell pool isolated from LGG tumor contains a heterogeneous population consisting tumor cells at various stages of tumor progression including cells with early genetic lesions if any prior to acquisition of IDH1 mutation. Because cells containing IDH1 mutation are refractory to reprogramming, we predict that iPSC clones should originate only from LGG cells without IDH1 mutation, i.e. cells prior to acquisition of IDH1 mutation. As expected, we found that none of the iPSC clones contains IDH1 mutation. Further analysis by aCGH of the iPSC clones reveals that they contain regional chromosomal amplifications which are also present in the primary LGG cells. Conclusions: These results indicate that there exists a subpopulation of cells harboring gene amplification but without IDH1 mutation in the LGG primary cell pool. Further analysis of TCGA LGG database demonstrates that these regional chromosomal amplifications are also present in some cases of low grade gliomas indicating they are reoccurring lesions in glioma albeit at a low frequency. Taken together, these data suggest that regional chromosomal alterations may exist prior to the acquisition of IDH mutations in at least some cases of LGGs.

Original languageEnglish (US)
JournalJournal of Neuro-Oncology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Glioma
Mutation
Clone Cells
Comparative Genomic Hybridization
Transcription Factors
Neoplasms
Genetic Loci
Gene Amplification
Epigenomics
Databases

Keywords

  • Gliomagenesis
  • IDH1
  • Induced pluripotent stem cells
  • Low-grade glioma
  • Regional chromosomal amplification

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Characterization of iPSCs derived from low grade gliomas revealed early regional chromosomal amplifications during gliomagenesis. / Liu, Zhong; Che, Pulin; Mercado, Juan J.; Hackney, James R.; Friedman, Gregory K.; Zhang, Cheng; You, Zhiying; Zhao, Xinyang; Ding, Qiang; Kim, Kitai; Li, Hu; Liu, Xiaoguang; Markert, James M.; Nabors, Burt; Gillespie, G. Yancey; Zhao, Rui; Han, Xiaosi.

In: Journal of Neuro-Oncology, 01.01.2018.

Research output: Contribution to journalArticle

Liu, Z, Che, P, Mercado, JJ, Hackney, JR, Friedman, GK, Zhang, C, You, Z, Zhao, X, Ding, Q, Kim, K, Li, H, Liu, X, Markert, JM, Nabors, B, Gillespie, GY, Zhao, R & Han, X 2018, 'Characterization of iPSCs derived from low grade gliomas revealed early regional chromosomal amplifications during gliomagenesis', Journal of Neuro-Oncology. https://doi.org/10.1007/s11060-018-03047-1
Liu, Zhong ; Che, Pulin ; Mercado, Juan J. ; Hackney, James R. ; Friedman, Gregory K. ; Zhang, Cheng ; You, Zhiying ; Zhao, Xinyang ; Ding, Qiang ; Kim, Kitai ; Li, Hu ; Liu, Xiaoguang ; Markert, James M. ; Nabors, Burt ; Gillespie, G. Yancey ; Zhao, Rui ; Han, Xiaosi. / Characterization of iPSCs derived from low grade gliomas revealed early regional chromosomal amplifications during gliomagenesis. In: Journal of Neuro-Oncology. 2018.
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abstract = "Introduction: IDH1 mutation has been identified as an early genetic event driving low grade gliomas (LGGs) and it has been proven to exerts a powerful epigenetic effect. Cells containing IDH1 mutation are refractory to epigenetical reprogramming to iPSC induced by expression of Yamanaka transcription factors, a feature that we employed to study early genetic amplifications or deletions in gliomagenesis. Methods: We made iPSC clones from freshly surgically resected IDH1 mutant LGGs by forced expression of Yamanaka transcription factors. We sequenced the IDH locus and analyzed the genetic composition of multiple iPSC clones by array-based comparative genomic hybridization (aCGH). Results: We hypothesize that the primary cell pool isolated from LGG tumor contains a heterogeneous population consisting tumor cells at various stages of tumor progression including cells with early genetic lesions if any prior to acquisition of IDH1 mutation. Because cells containing IDH1 mutation are refractory to reprogramming, we predict that iPSC clones should originate only from LGG cells without IDH1 mutation, i.e. cells prior to acquisition of IDH1 mutation. As expected, we found that none of the iPSC clones contains IDH1 mutation. Further analysis by aCGH of the iPSC clones reveals that they contain regional chromosomal amplifications which are also present in the primary LGG cells. Conclusions: These results indicate that there exists a subpopulation of cells harboring gene amplification but without IDH1 mutation in the LGG primary cell pool. Further analysis of TCGA LGG database demonstrates that these regional chromosomal amplifications are also present in some cases of low grade gliomas indicating they are reoccurring lesions in glioma albeit at a low frequency. Taken together, these data suggest that regional chromosomal alterations may exist prior to the acquisition of IDH mutations in at least some cases of LGGs.",
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AU - Liu, Zhong

AU - Che, Pulin

AU - Mercado, Juan J.

AU - Hackney, James R.

AU - Friedman, Gregory K.

AU - Zhang, Cheng

AU - You, Zhiying

AU - Zhao, Xinyang

AU - Ding, Qiang

AU - Kim, Kitai

AU - Li, Hu

AU - Liu, Xiaoguang

AU - Markert, James M.

AU - Nabors, Burt

AU - Gillespie, G. Yancey

AU - Zhao, Rui

AU - Han, Xiaosi

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N2 - Introduction: IDH1 mutation has been identified as an early genetic event driving low grade gliomas (LGGs) and it has been proven to exerts a powerful epigenetic effect. Cells containing IDH1 mutation are refractory to epigenetical reprogramming to iPSC induced by expression of Yamanaka transcription factors, a feature that we employed to study early genetic amplifications or deletions in gliomagenesis. Methods: We made iPSC clones from freshly surgically resected IDH1 mutant LGGs by forced expression of Yamanaka transcription factors. We sequenced the IDH locus and analyzed the genetic composition of multiple iPSC clones by array-based comparative genomic hybridization (aCGH). Results: We hypothesize that the primary cell pool isolated from LGG tumor contains a heterogeneous population consisting tumor cells at various stages of tumor progression including cells with early genetic lesions if any prior to acquisition of IDH1 mutation. Because cells containing IDH1 mutation are refractory to reprogramming, we predict that iPSC clones should originate only from LGG cells without IDH1 mutation, i.e. cells prior to acquisition of IDH1 mutation. As expected, we found that none of the iPSC clones contains IDH1 mutation. Further analysis by aCGH of the iPSC clones reveals that they contain regional chromosomal amplifications which are also present in the primary LGG cells. Conclusions: These results indicate that there exists a subpopulation of cells harboring gene amplification but without IDH1 mutation in the LGG primary cell pool. Further analysis of TCGA LGG database demonstrates that these regional chromosomal amplifications are also present in some cases of low grade gliomas indicating they are reoccurring lesions in glioma albeit at a low frequency. Taken together, these data suggest that regional chromosomal alterations may exist prior to the acquisition of IDH mutations in at least some cases of LGGs.

AB - Introduction: IDH1 mutation has been identified as an early genetic event driving low grade gliomas (LGGs) and it has been proven to exerts a powerful epigenetic effect. Cells containing IDH1 mutation are refractory to epigenetical reprogramming to iPSC induced by expression of Yamanaka transcription factors, a feature that we employed to study early genetic amplifications or deletions in gliomagenesis. Methods: We made iPSC clones from freshly surgically resected IDH1 mutant LGGs by forced expression of Yamanaka transcription factors. We sequenced the IDH locus and analyzed the genetic composition of multiple iPSC clones by array-based comparative genomic hybridization (aCGH). Results: We hypothesize that the primary cell pool isolated from LGG tumor contains a heterogeneous population consisting tumor cells at various stages of tumor progression including cells with early genetic lesions if any prior to acquisition of IDH1 mutation. Because cells containing IDH1 mutation are refractory to reprogramming, we predict that iPSC clones should originate only from LGG cells without IDH1 mutation, i.e. cells prior to acquisition of IDH1 mutation. As expected, we found that none of the iPSC clones contains IDH1 mutation. Further analysis by aCGH of the iPSC clones reveals that they contain regional chromosomal amplifications which are also present in the primary LGG cells. Conclusions: These results indicate that there exists a subpopulation of cells harboring gene amplification but without IDH1 mutation in the LGG primary cell pool. Further analysis of TCGA LGG database demonstrates that these regional chromosomal amplifications are also present in some cases of low grade gliomas indicating they are reoccurring lesions in glioma albeit at a low frequency. Taken together, these data suggest that regional chromosomal alterations may exist prior to the acquisition of IDH mutations in at least some cases of LGGs.

KW - Gliomagenesis

KW - IDH1

KW - Induced pluripotent stem cells

KW - Low-grade glioma

KW - Regional chromosomal amplification

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