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IMG-12. CHARACTERISATION OF MODELS OF H3F3A_G34R/V MUTANT PAEDIATRIC GLIOBLASTOMA IN VIVO USING MAGNETIC RESONANCE IMAGING

Approximately 15% of paediatric/young adult cerebral hemispheric glioblastomas (pGBM) harbour G34R/V mutations in H3F3A, encoding the histone H3.3 variant. Development of novel therapeutic interventions demands models that accurately recapitulate this subset of disease and sensitive imaging methods...

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Autores principales: Boult, Jessica, Bjerke, Lynn, Fofana, Mariama, Vinci, Maria, Molinari, Valeria, Mackay, Alan, Temelso, Sara, Box, Gary, Eccles, Suzanne, Carcaboso, Angel, Castro, Maria, Waanders, Angela, Cole, Kristina, Jones, Chris, Robinson, Simon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715122/
http://dx.doi.org/10.1093/neuonc/noaa222.347
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author Boult, Jessica
Bjerke, Lynn
Fofana, Mariama
Vinci, Maria
Molinari, Valeria
Mackay, Alan
Temelso, Sara
Box, Gary
Eccles, Suzanne
Carcaboso, Angel
Castro, Maria
Waanders, Angela
Cole, Kristina
Jones, Chris
Robinson, Simon
author_facet Boult, Jessica
Bjerke, Lynn
Fofana, Mariama
Vinci, Maria
Molinari, Valeria
Mackay, Alan
Temelso, Sara
Box, Gary
Eccles, Suzanne
Carcaboso, Angel
Castro, Maria
Waanders, Angela
Cole, Kristina
Jones, Chris
Robinson, Simon
author_sort Boult, Jessica
collection PubMed
description Approximately 15% of paediatric/young adult cerebral hemispheric glioblastomas (pGBM) harbour G34R/V mutations in H3F3A, encoding the histone H3.3 variant. Development of novel therapeutic interventions demands models that accurately recapitulate this subset of disease and sensitive imaging methods with which to study tumours in situ. Three H3F3A_G34R primary-patient-derived cultures, alongside established cell-line KNS42 (H3F3A_G34V), were implanted orthotopically in immunocompromised mice. KNS42 (TP53_R342*) tumours were clearly detectable using T(2-)weighted (T(2)w)-MRI, enhanced following contrast agent administration, indicating impaired blood-brain barrier (BBB) integrity, and demonstrated minimal invasion. OPBG_GBM_001 cells (TP53_89-90X,ATRX_II2133-2144X) formed infiltrative tumours that were hyperintense on T(2)w-MRI and demonstrated contrast-enhancement suggestive of heterogeneous BBB integrity. HSJD_GBM_002 cells (TP53_P278T,ATRX_R666*) spread diffusely throughout the brain with their full extent typically not discernible by T(2)w-MRI, the BBB also remaining intact. No evidence of CHOP_GBM_001 tumour was detected by MRI 11months post-implantation. Immunocompetent syngeneic models using tumour cells induced by mutations modelling hemispheric pGBM (NRAS/shP53/shATRX±H3.3G34R) are being explored. Fast growing heterogeneous lesions with variable contrast-enhancement were identified; the H3.3G34R mutation conferred longer median survival (2 clones:25/28days, control:14days). These models have the advantage of an intact immune system and short latency for initial efficacy studies. Primary pGBM cells yield tumours that are more representative of the spectrum of clinical disease; variable hyperintensity on T(2)w-MRI corresponding to cellular density, with diffusely infiltrative disease less clearly definable, a paucity of oedema and a range of contrast-enhancement. Pathological features including giant multinucleated cells, and mitotic figures were also evident.
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spelling pubmed-77151222020-12-09 IMG-12. CHARACTERISATION OF MODELS OF H3F3A_G34R/V MUTANT PAEDIATRIC GLIOBLASTOMA IN VIVO USING MAGNETIC RESONANCE IMAGING Boult, Jessica Bjerke, Lynn Fofana, Mariama Vinci, Maria Molinari, Valeria Mackay, Alan Temelso, Sara Box, Gary Eccles, Suzanne Carcaboso, Angel Castro, Maria Waanders, Angela Cole, Kristina Jones, Chris Robinson, Simon Neuro Oncol Imaging Approximately 15% of paediatric/young adult cerebral hemispheric glioblastomas (pGBM) harbour G34R/V mutations in H3F3A, encoding the histone H3.3 variant. Development of novel therapeutic interventions demands models that accurately recapitulate this subset of disease and sensitive imaging methods with which to study tumours in situ. Three H3F3A_G34R primary-patient-derived cultures, alongside established cell-line KNS42 (H3F3A_G34V), were implanted orthotopically in immunocompromised mice. KNS42 (TP53_R342*) tumours were clearly detectable using T(2-)weighted (T(2)w)-MRI, enhanced following contrast agent administration, indicating impaired blood-brain barrier (BBB) integrity, and demonstrated minimal invasion. OPBG_GBM_001 cells (TP53_89-90X,ATRX_II2133-2144X) formed infiltrative tumours that were hyperintense on T(2)w-MRI and demonstrated contrast-enhancement suggestive of heterogeneous BBB integrity. HSJD_GBM_002 cells (TP53_P278T,ATRX_R666*) spread diffusely throughout the brain with their full extent typically not discernible by T(2)w-MRI, the BBB also remaining intact. No evidence of CHOP_GBM_001 tumour was detected by MRI 11months post-implantation. Immunocompetent syngeneic models using tumour cells induced by mutations modelling hemispheric pGBM (NRAS/shP53/shATRX±H3.3G34R) are being explored. Fast growing heterogeneous lesions with variable contrast-enhancement were identified; the H3.3G34R mutation conferred longer median survival (2 clones:25/28days, control:14days). These models have the advantage of an intact immune system and short latency for initial efficacy studies. Primary pGBM cells yield tumours that are more representative of the spectrum of clinical disease; variable hyperintensity on T(2)w-MRI corresponding to cellular density, with diffusely infiltrative disease less clearly definable, a paucity of oedema and a range of contrast-enhancement. Pathological features including giant multinucleated cells, and mitotic figures were also evident. Oxford University Press 2020-12-04 /pmc/articles/PMC7715122/ http://dx.doi.org/10.1093/neuonc/noaa222.347 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://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 Imaging
Boult, Jessica
Bjerke, Lynn
Fofana, Mariama
Vinci, Maria
Molinari, Valeria
Mackay, Alan
Temelso, Sara
Box, Gary
Eccles, Suzanne
Carcaboso, Angel
Castro, Maria
Waanders, Angela
Cole, Kristina
Jones, Chris
Robinson, Simon
IMG-12. CHARACTERISATION OF MODELS OF H3F3A_G34R/V MUTANT PAEDIATRIC GLIOBLASTOMA IN VIVO USING MAGNETIC RESONANCE IMAGING
title IMG-12. CHARACTERISATION OF MODELS OF H3F3A_G34R/V MUTANT PAEDIATRIC GLIOBLASTOMA IN VIVO USING MAGNETIC RESONANCE IMAGING
title_full IMG-12. CHARACTERISATION OF MODELS OF H3F3A_G34R/V MUTANT PAEDIATRIC GLIOBLASTOMA IN VIVO USING MAGNETIC RESONANCE IMAGING
title_fullStr IMG-12. CHARACTERISATION OF MODELS OF H3F3A_G34R/V MUTANT PAEDIATRIC GLIOBLASTOMA IN VIVO USING MAGNETIC RESONANCE IMAGING
title_full_unstemmed IMG-12. CHARACTERISATION OF MODELS OF H3F3A_G34R/V MUTANT PAEDIATRIC GLIOBLASTOMA IN VIVO USING MAGNETIC RESONANCE IMAGING
title_short IMG-12. CHARACTERISATION OF MODELS OF H3F3A_G34R/V MUTANT PAEDIATRIC GLIOBLASTOMA IN VIVO USING MAGNETIC RESONANCE IMAGING
title_sort img-12. characterisation of models of h3f3a_g34r/v mutant paediatric glioblastoma in vivo using magnetic resonance imaging
topic Imaging
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7715122/
http://dx.doi.org/10.1093/neuonc/noaa222.347
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