H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines

High-grade gliomas represent the most lethal class of pediatric tumors, and their resistance to both radio- and chemotherapy is associated with a poor prognosis. Recurrent mutations affecting histone genes drive the tumorigenesis of some pediatric high-grade gliomas, and H3K27M mutations are notably...

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Autores principales:	Andria Rakotomalala, Quentin Bailleul, Clara Savary, Mélanie Arcicasa, Maud Hamadou, Paul Huchedé, Audrey Hochart, Audrey Restouin, Remy Castellano, Yves Collette, Emma Dieny, Audrey Vincent, Pierre-Olivier Angrand, Xuefen Le Bourhis, Pierre Leblond, Alessandro Furlan, Marie Castets, Eddy Pasquier, Samuel Meignan
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	H3.3K27M glioma child resistance to therapies radiotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/42cf81e91f7b4d65b7024047c01962a6
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spelling	oai:doaj.org-article:42cf81e91f7b4d65b7024047c01962a62021-11-11T15:34:43ZH3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines10.3390/cancers132155512072-6694https://doaj.org/article/42cf81e91f7b4d65b7024047c01962a62021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5551https://doaj.org/toc/2072-6694High-grade gliomas represent the most lethal class of pediatric tumors, and their resistance to both radio- and chemotherapy is associated with a poor prognosis. Recurrent mutations affecting histone genes drive the tumorigenesis of some pediatric high-grade gliomas, and H3K27M mutations are notably characteristic of a subtype of gliomas called DMG (Diffuse Midline Gliomas). This dominant negative mutation impairs H3K27 trimethylation, leading to profound epigenetic modifications of genes expression. Even though this mutation was described as a driver event in tumorigenesis, its role in tumor cell resistance to treatments has not been deciphered so far. To tackle this issue, we expressed the H3.3K27M mutated histone in three initially H3K27-unmutated pediatric glioma cell lines, Res259, SF188, and KNS42. First, we validated these new H3.3K27M-expressing models at the molecular level and showed that K27M expression is associated with pleiotropic effects on the transcriptomic signature, largely dependent on cell context. We observed that the mutation triggered an increase in cell growth in Res259 and SF188 cells, associated with higher clonogenic capacities. Interestingly, we evidenced that the mutation confers an increased resistance to ionizing radiations in Res259 and KNS42 cells. Moreover, we showed that H3.3K27M mutation impacts the sensitivity of Res259 cells to specific drugs among a library of 80 anticancerous compounds. Altogether, these data highlight that, beyond its tumorigenic role, H3.3K27M mutation is strongly involved in pediatric glioma cells’ resistance to therapies, likely through transcriptomic reprogramming.Andria RakotomalalaQuentin BailleulClara SavaryMélanie ArcicasaMaud HamadouPaul HuchedéAudrey HochartAudrey RestouinRemy CastellanoYves ColletteEmma DienyAudrey VincentPierre-Olivier AngrandXuefen Le BourhisPierre LeblondAlessandro FurlanMarie CastetsEddy PasquierSamuel MeignanMDPI AGarticleH3.3K27Mgliomachildresistance to therapiesradiotherapyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5551, p 5551 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	H3.3K27M glioma child resistance to therapies radiotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	H3.3K27M glioma child resistance to therapies radiotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Andria Rakotomalala Quentin Bailleul Clara Savary Mélanie Arcicasa Maud Hamadou Paul Huchedé Audrey Hochart Audrey Restouin Remy Castellano Yves Collette Emma Dieny Audrey Vincent Pierre-Olivier Angrand Xuefen Le Bourhis Pierre Leblond Alessandro Furlan Marie Castets Eddy Pasquier Samuel Meignan H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines
description	High-grade gliomas represent the most lethal class of pediatric tumors, and their resistance to both radio- and chemotherapy is associated with a poor prognosis. Recurrent mutations affecting histone genes drive the tumorigenesis of some pediatric high-grade gliomas, and H3K27M mutations are notably characteristic of a subtype of gliomas called DMG (Diffuse Midline Gliomas). This dominant negative mutation impairs H3K27 trimethylation, leading to profound epigenetic modifications of genes expression. Even though this mutation was described as a driver event in tumorigenesis, its role in tumor cell resistance to treatments has not been deciphered so far. To tackle this issue, we expressed the H3.3K27M mutated histone in three initially H3K27-unmutated pediatric glioma cell lines, Res259, SF188, and KNS42. First, we validated these new H3.3K27M-expressing models at the molecular level and showed that K27M expression is associated with pleiotropic effects on the transcriptomic signature, largely dependent on cell context. We observed that the mutation triggered an increase in cell growth in Res259 and SF188 cells, associated with higher clonogenic capacities. Interestingly, we evidenced that the mutation confers an increased resistance to ionizing radiations in Res259 and KNS42 cells. Moreover, we showed that H3.3K27M mutation impacts the sensitivity of Res259 cells to specific drugs among a library of 80 anticancerous compounds. Altogether, these data highlight that, beyond its tumorigenic role, H3.3K27M mutation is strongly involved in pediatric glioma cells’ resistance to therapies, likely through transcriptomic reprogramming.
format	article
author	Andria Rakotomalala Quentin Bailleul Clara Savary Mélanie Arcicasa Maud Hamadou Paul Huchedé Audrey Hochart Audrey Restouin Remy Castellano Yves Collette Emma Dieny Audrey Vincent Pierre-Olivier Angrand Xuefen Le Bourhis Pierre Leblond Alessandro Furlan Marie Castets Eddy Pasquier Samuel Meignan
author_facet	Andria Rakotomalala Quentin Bailleul Clara Savary Mélanie Arcicasa Maud Hamadou Paul Huchedé Audrey Hochart Audrey Restouin Remy Castellano Yves Collette Emma Dieny Audrey Vincent Pierre-Olivier Angrand Xuefen Le Bourhis Pierre Leblond Alessandro Furlan Marie Castets Eddy Pasquier Samuel Meignan
author_sort	Andria Rakotomalala
title	H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines
title_short	H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines
title_full	H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines
title_fullStr	H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines
title_full_unstemmed	H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines
title_sort	h3.3k27m mutation controls cell growth and resistance to therapies in pediatric glioma cell lines
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/42cf81e91f7b4d65b7024047c01962a6
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H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines

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