DIPG-47. DISCOVERING A MOLECULAR BASIS FOR VULNERABILITY OF H3K27M-DMG TO HISTONE DEACETYLASE INHIBITORS
نویسندگان
چکیده
Abstract Using two H3K27M-DMG treatment-naive preclinical models (PBT22 and PBT29), we detected a 20-fold differential response to the histone deacetylase inhibitor, Quisinostat. PBT-22 harbors mutations in H3F3A, TP53, ASXL2, while PBT-29 has PIK3CA FGFR1. Acetylation deacetylation of wtH3 alter chromatin structure as part normal regulation gene expression. The methionine substitution for Lysine H3K27M removes this from participating acetylation/deacetylation regulated Concomitantly, induces marked reduction global acetylation tails on wtH3. In native state DMG with hypoacetylated H3, posit that specific pattern nucleosome integration genes responsible cell survival/death underlies vulnerability DMGs HDACi. Additionally, may be based relative abundance wtH3wt versus H3K27M- histones. Following Quis treatment (48 hrs) both models, total wtH3ac protein increased 3-fold, suggesting HDACi stabilizes or impedes K27 acetylated H3 turnover. Comparison differentially expressed (DEGs) control Quis-treated PBT22 PBT29 will seed ontology analysis focusing remodeling, death, growth arrest pathways accounting vulnerability. Findings validated by measuring transcripts proteins (qRT-PCR ELISA mass spectrometry) analytes larger panel lines. data depicts large sensitivity Quis. long-term goal is discover molecular profile predictive discovery exercise also likely yield insight into development resistance HDAC inhibitors.
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ژورنال
عنوان ژورنال: Neuro-oncology
سال: 2023
ISSN: ['1523-5866', '1522-8517']
DOI: https://doi.org/10.1093/neuonc/noad073.094