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Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma

Glioblastoma is the most prevalent primary malignant brain tumor in adults and is characterized by poor prognosis and universal tumor recurrence. Effective glioblastoma treatments are lacking, in part due to somatic mutations and epigenetic reprogramming that alter gene expression and confer drug re...

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Autores principales: Sen, Arko, Prager, Briana C., Zhong, Cuiqing, Park, Donglim, Zhu, Zhe, Gimple, Ryan C., Wu, Qiulian, Bernatchez, Jean A., Beck, Sungjun, Clark, Alex E., Siqueira-Neto, Jair L., Rich, Jeremy N., McVicker, Graham
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122831/
https://www.ncbi.nlm.nih.gov/pubmed/34903607
http://dx.doi.org/10.1158/0008-5472.CAN-21-0810
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author Sen, Arko
Prager, Briana C.
Zhong, Cuiqing
Park, Donglim
Zhu, Zhe
Gimple, Ryan C.
Wu, Qiulian
Bernatchez, Jean A.
Beck, Sungjun
Clark, Alex E.
Siqueira-Neto, Jair L.
Rich, Jeremy N.
McVicker, Graham
author_facet Sen, Arko
Prager, Briana C.
Zhong, Cuiqing
Park, Donglim
Zhu, Zhe
Gimple, Ryan C.
Wu, Qiulian
Bernatchez, Jean A.
Beck, Sungjun
Clark, Alex E.
Siqueira-Neto, Jair L.
Rich, Jeremy N.
McVicker, Graham
author_sort Sen, Arko
collection PubMed
description Glioblastoma is the most prevalent primary malignant brain tumor in adults and is characterized by poor prognosis and universal tumor recurrence. Effective glioblastoma treatments are lacking, in part due to somatic mutations and epigenetic reprogramming that alter gene expression and confer drug resistance. To investigate recurrently dysregulated genes in glioblastoma, we interrogated allele-specific expression (ASE), the difference in expression between two alleles of a gene, in glioblastoma stem cells (GSC) derived from 43 patients. A total of 118 genes were found with recurrent ASE preferentially in GSCs compared with normal tissues. These genes were enriched for apoptotic regulators, including schlafen family member 11 (SLFN11). Loss of SLFN11 gene expression was associated with aberrant promoter methylation and conferred resistance to chemotherapy and PARP inhibition. Conversely, low SLFN11 expression rendered GSCs susceptible to the oncolytic flavivirus Zika. This discovery effort based upon ASE revealed novel points of vulnerability in GSCs, suggesting a potential alternative treatment strategy for chemotherapy-resistant glioblastoma. SIGNIFICANCE: Assessing allele-specific expression reveals genes with recurrent cis-regulatory changes that are enriched in glioblastoma stem cells, including SLFN11, which modulates chemotherapy resistance and susceptibility to the oncolytic Zika virus.
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spelling pubmed-91228312022-05-21 Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma Sen, Arko Prager, Briana C. Zhong, Cuiqing Park, Donglim Zhu, Zhe Gimple, Ryan C. Wu, Qiulian Bernatchez, Jean A. Beck, Sungjun Clark, Alex E. Siqueira-Neto, Jair L. Rich, Jeremy N. McVicker, Graham Cancer Res Genome and Epigenome Glioblastoma is the most prevalent primary malignant brain tumor in adults and is characterized by poor prognosis and universal tumor recurrence. Effective glioblastoma treatments are lacking, in part due to somatic mutations and epigenetic reprogramming that alter gene expression and confer drug resistance. To investigate recurrently dysregulated genes in glioblastoma, we interrogated allele-specific expression (ASE), the difference in expression between two alleles of a gene, in glioblastoma stem cells (GSC) derived from 43 patients. A total of 118 genes were found with recurrent ASE preferentially in GSCs compared with normal tissues. These genes were enriched for apoptotic regulators, including schlafen family member 11 (SLFN11). Loss of SLFN11 gene expression was associated with aberrant promoter methylation and conferred resistance to chemotherapy and PARP inhibition. Conversely, low SLFN11 expression rendered GSCs susceptible to the oncolytic flavivirus Zika. This discovery effort based upon ASE revealed novel points of vulnerability in GSCs, suggesting a potential alternative treatment strategy for chemotherapy-resistant glioblastoma. SIGNIFICANCE: Assessing allele-specific expression reveals genes with recurrent cis-regulatory changes that are enriched in glioblastoma stem cells, including SLFN11, which modulates chemotherapy resistance and susceptibility to the oncolytic Zika virus. American Association for Cancer Research 2022-02-01 2021-12-13 /pmc/articles/PMC9122831/ /pubmed/34903607 http://dx.doi.org/10.1158/0008-5472.CAN-21-0810 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Genome and Epigenome
Sen, Arko
Prager, Briana C.
Zhong, Cuiqing
Park, Donglim
Zhu, Zhe
Gimple, Ryan C.
Wu, Qiulian
Bernatchez, Jean A.
Beck, Sungjun
Clark, Alex E.
Siqueira-Neto, Jair L.
Rich, Jeremy N.
McVicker, Graham
Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma
title Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma
title_full Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma
title_fullStr Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma
title_full_unstemmed Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma
title_short Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma
title_sort leveraging allele-specific expression for therapeutic response gene discovery in glioblastoma
topic Genome and Epigenome
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122831/
https://www.ncbi.nlm.nih.gov/pubmed/34903607
http://dx.doi.org/10.1158/0008-5472.CAN-21-0810
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