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LGG-45. Genetic dependencies inMYB/MYBL1-driven pediatric low-grade glioma models

AIM: Pediatric low-grade gliomas (pLGGs) are a heterogenous group of tumors, diverse in their localization, histology, mutational landscape, clinical behavior, and treatment response. Genomic alterations impacting the MYB family of transcription factors were identified in two distinct pLGG subtypes:...

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Autores principales: Condurat, Alexandra-Larisa, Jones, Jill, Gonzalez, Elizabeth, Doshi, Jeyna, Zhou, Kevin, Tsai, Jessica W, Khadka, Prasidda, Buchan, Graham B J, Rouleau, Cecile, Pelton, Kristine, Abid, Tanaz, Goodale, Amy, Persky, Nicole, Beroukhim, Rameen, Ligon, Keith, Root, David, Piccioni, Federica, Bandopadhayay, Pratiti
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164946/
http://dx.doi.org/10.1093/neuonc/noac079.357
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author Condurat, Alexandra-Larisa
Jones, Jill
Gonzalez, Elizabeth
Doshi, Jeyna
Zhou, Kevin
Tsai, Jessica W
Khadka, Prasidda
Buchan, Graham B J
Rouleau, Cecile
Pelton, Kristine
Abid, Tanaz
Goodale, Amy
Persky, Nicole
Beroukhim, Rameen
Ligon, Keith
Root, David
Piccioni, Federica
Bandopadhayay, Pratiti
author_facet Condurat, Alexandra-Larisa
Jones, Jill
Gonzalez, Elizabeth
Doshi, Jeyna
Zhou, Kevin
Tsai, Jessica W
Khadka, Prasidda
Buchan, Graham B J
Rouleau, Cecile
Pelton, Kristine
Abid, Tanaz
Goodale, Amy
Persky, Nicole
Beroukhim, Rameen
Ligon, Keith
Root, David
Piccioni, Federica
Bandopadhayay, Pratiti
author_sort Condurat, Alexandra-Larisa
collection PubMed
description AIM: Pediatric low-grade gliomas (pLGGs) are a heterogenous group of tumors, diverse in their localization, histology, mutational landscape, clinical behavior, and treatment response. Genomic alterations impacting the MYB family of transcription factors were identified in two distinct pLGG subtypes: Angiocentric Gliomas (AG) and Diffuse Astrocytomas (DA). The molecular profiles and therapeutic vulnerabilities associated with these genomic alterations remain unexplored. In this study we highlight the use of genome-wide CRISPR/Cas9 knock-out screens for an unbiased identification of translatable therapeutic targets. METHODOLOGY: Given the lack of patient-derived pLGG cell lines, we engineered in vitro pLGG mouse and human neural stem cell (NSC) models to harbor pLGG-relevant genomic alterations. We performed single cell RNA sequencing to investigate the transcriptional profiles driven by these mutations and to dissect the central regulatory networks enabling tumorigenesis. Specific genetic dependencies associated with MYB/MYBL1 mutations were screened using the Brie genome-wide mouse CRISPR lentiviral knock-out pooled library, consisting of 78,637 single guide RNAs (sgRNAs) targeting 19,674 mouse genes. RESULTS: We have successfully generated in vitro NSC-based pLGG models crucial to deepening our knowledge on pLGG biology and the identification of translatable therapeutic targets. Genome-scale CRISPR/Cas9 knock-out screens in isogenic NSCs models, expressing distinct MYB/MYBL1 alterations or a control transgene, revealed several differential genetic dependencies. Among the top identified dependencies are regulators of cell-stress response, cell-cycle progression, and modulators of the ubiquitin-proteasome degradation pathway. CONCLUSION: Genome-wide CRISPR knock-out screens are a powerful tool for the unbiased identification of mutation-specific genetic dependencies that can be explored as candidates for precision medicine approaches.
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spelling pubmed-91649462022-06-05 LGG-45. Genetic dependencies inMYB/MYBL1-driven pediatric low-grade glioma models Condurat, Alexandra-Larisa Jones, Jill Gonzalez, Elizabeth Doshi, Jeyna Zhou, Kevin Tsai, Jessica W Khadka, Prasidda Buchan, Graham B J Rouleau, Cecile Pelton, Kristine Abid, Tanaz Goodale, Amy Persky, Nicole Beroukhim, Rameen Ligon, Keith Root, David Piccioni, Federica Bandopadhayay, Pratiti Neuro Oncol Low Grade Glioma AIM: Pediatric low-grade gliomas (pLGGs) are a heterogenous group of tumors, diverse in their localization, histology, mutational landscape, clinical behavior, and treatment response. Genomic alterations impacting the MYB family of transcription factors were identified in two distinct pLGG subtypes: Angiocentric Gliomas (AG) and Diffuse Astrocytomas (DA). The molecular profiles and therapeutic vulnerabilities associated with these genomic alterations remain unexplored. In this study we highlight the use of genome-wide CRISPR/Cas9 knock-out screens for an unbiased identification of translatable therapeutic targets. METHODOLOGY: Given the lack of patient-derived pLGG cell lines, we engineered in vitro pLGG mouse and human neural stem cell (NSC) models to harbor pLGG-relevant genomic alterations. We performed single cell RNA sequencing to investigate the transcriptional profiles driven by these mutations and to dissect the central regulatory networks enabling tumorigenesis. Specific genetic dependencies associated with MYB/MYBL1 mutations were screened using the Brie genome-wide mouse CRISPR lentiviral knock-out pooled library, consisting of 78,637 single guide RNAs (sgRNAs) targeting 19,674 mouse genes. RESULTS: We have successfully generated in vitro NSC-based pLGG models crucial to deepening our knowledge on pLGG biology and the identification of translatable therapeutic targets. Genome-scale CRISPR/Cas9 knock-out screens in isogenic NSCs models, expressing distinct MYB/MYBL1 alterations or a control transgene, revealed several differential genetic dependencies. Among the top identified dependencies are regulators of cell-stress response, cell-cycle progression, and modulators of the ubiquitin-proteasome degradation pathway. CONCLUSION: Genome-wide CRISPR knock-out screens are a powerful tool for the unbiased identification of mutation-specific genetic dependencies that can be explored as candidates for precision medicine approaches. Oxford University Press 2022-06-03 /pmc/articles/PMC9164946/ http://dx.doi.org/10.1093/neuonc/noac079.357 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Low Grade Glioma
Condurat, Alexandra-Larisa
Jones, Jill
Gonzalez, Elizabeth
Doshi, Jeyna
Zhou, Kevin
Tsai, Jessica W
Khadka, Prasidda
Buchan, Graham B J
Rouleau, Cecile
Pelton, Kristine
Abid, Tanaz
Goodale, Amy
Persky, Nicole
Beroukhim, Rameen
Ligon, Keith
Root, David
Piccioni, Federica
Bandopadhayay, Pratiti
LGG-45. Genetic dependencies inMYB/MYBL1-driven pediatric low-grade glioma models
title LGG-45. Genetic dependencies inMYB/MYBL1-driven pediatric low-grade glioma models
title_full LGG-45. Genetic dependencies inMYB/MYBL1-driven pediatric low-grade glioma models
title_fullStr LGG-45. Genetic dependencies inMYB/MYBL1-driven pediatric low-grade glioma models
title_full_unstemmed LGG-45. Genetic dependencies inMYB/MYBL1-driven pediatric low-grade glioma models
title_short LGG-45. Genetic dependencies inMYB/MYBL1-driven pediatric low-grade glioma models
title_sort lgg-45. genetic dependencies inmyb/mybl1-driven pediatric low-grade glioma models
topic Low Grade Glioma
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164946/
http://dx.doi.org/10.1093/neuonc/noac079.357
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