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2 results on '"Chibo Hong"'

1. DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors

Author

Susan M. Chang, Joseph F. Costello, Annette M. Molinaro, Martine L.M. Lamfers, Tali Mazor, Ivan Smirnov, Emily G. Hamilton, Ahmed Idbaih, Robert J.A. Bell, Chibo Hong, Jun S. Song, Brett E. Johnson, Aleksandr Pankov, Barry S. Taylor, Agusti Alentorn, Gerald F. Reis, Michael J. Barnes, Adam B. Olshen, Jenneke Kloezeman, Joanna J. Phillips, Andrew W. Bollen, and Neurosurgery

Subjects
Cancer Research, Transcription, Genetic, Somatic cell, medicine.disease_cause, Epigenesis, Genetic, 0302 clinical medicine, Promoter Regions, Genetic, Phylogeny, Cancer, Genetics, Regulation of gene expression, 0303 health sciences, Mutation, Brain Neoplasms, Glioma, Cell cycle, Up-Regulation, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Transcription, Biotechnology, Oncology and Carcinogenesis, Biology, Article, Promoter Regions, 03 medical and health sciences, Rare Diseases, Genetic, medicine, Humans, Epigenetics, Oncology & Carcinogenesis, Gene, 030304 developmental biology, Neoplastic, Human Genome, Neurosciences, Cell Biology, DNA Methylation, medicine.disease, G1 Phase Cell Cycle Checkpoints, Brain Disorders, Brain Cancer, Gene Expression Regulation, Glioblastoma, Epigenesis
Abstract

SummaryThe evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to stable genetic events, epigenetic states are reversible and sensitive to the microenvironment, prompting the question whether epigenetic information can similarly be used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes transcriptionally upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.

Published
2015

2. Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner

Author

Josie Hayes, Kyle M. Walsh, Joseph F. Costello, Christof Fellmann, Michael Gapinske, Robert J.A. Bell, Jennifer A. Doudna, Wendy S. Woods, Bruno M. Costa, Chibo Hong, Kien Thiet Nguyen, Pablo Perez-Pinera, Ana Xavier-Magalhães, Alexandra M. Amen, Andrew McKinney, Andrew Mancini, Lindsey E Jones, Jun S. Song, and Universidade do Minho

Subjects
0301 basic medicine, Male, Cancer Research, Telomerase, GABP, Medicina Básica [Ciências Médicas], Nude, Mutant, Mice, Cancer immortality, Tumor Cells, Cultured, Protein Isoforms, TERT promoter mutation, RNA, Small Interfering, Promoter Regions, Genetic, Cancer, Cultured, Chemistry, Brain Neoplasms, Telomere, GA-Binding Protein Transcription Factor, Tumor Cells, 3. Good health, Cell biology, Telomeres, Oncology, Gene Knockdown Techniques, Ciências Médicas::Medicina Básica, cancer immortality, Female, Gene isoform, Programmed cell death, Oncology and Carcinogenesis, Primary Cell Culture, Mice, Nude, Small Interfering, telomerase, Article, Promoter Regions, 03 medical and health sciences, Rare Diseases, Genetic, Tetramer, Genetics, Gene silencing, Animals, Humans, Oncology & Carcinogenesis, Transcription factor, Science & Technology, glioblastoma, Neurosciences, telomeres, Survival Analysis, Xenograft Model Antitumor Assays, Brain Disorders, Brain Cancer, 030104 developmental biology, Mutation, RNA, Protein Multimerization, Glioblastoma
Abstract

TERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells. Orthotopic xenografting of β1L-reduced, TERT promoter mutant glioblastoma cells rendered lower tumor burden and longer overall survival in mice. These results highlight the critical role of GABPβ1L in enabling immortality in TERT promoter mutant glioblastoma., This work was supported by a generous gift from the Dabbiere family (J.F.C.), the Hana Jabsheh Research Initiative (J.F.C.), NIH grant NCI P50CA097257 (J.F.C. and J.A.D.), NCI P01CA118816-06 (J.F.C.), T32 GM008568 and T32 CA151022 (A.M.), and NCI R01CA163336 (J.S.S.), and the Sontag Foundation Distinguished Scientist Award (J.S.S.). C.F. is supported by a US NIH K99/R00 Pathway to Independence Award (K99GM118909) from the National Institute of General Medical Sciences. Additional support was provided by Fundação para a Ciência e Tecnologia SFRH/BD/88220/2012 (A.X.-M.) and IF/00601/2012 (B.M.C.). J.A.D. is an investigator of the Howard Hughes Medical Institute., info:eu-repo/semantics/publishedVersion

Published
2017

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