主旨
表观基因组
染色质
癌症研究
生物
转录因子
遗传学
作者
Matthew L. Hemming,Morgan R. Benson,Michael A Loycano,Justin A. Anderson,Jessica L. Andersen,Madeleine L Taddei,Andrei V. Krivtsov,Brandon J. Aubrey,Jevon A. Cutler,Charlie Hatton,Ewa Sicinska,Scott A. Armstrong
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2022-05-02
标识
DOI:10.1158/2159-8290.cd-21-0646
摘要
Abstract Gastrointestinal stromal tumor (GIST) is commonly characterized by activating mutations in the receptor tyrosine kinase KIT. Tyrosine kinase inhibitors are the only approved therapy for GIST, and complementary treatment strategies are urgently needed. As GIST lacks oncogene amplification and relies upon an established network of transcription factors, we hypothesized that unique chromatin modifying enzymes are essential in orchestrating the GIST epigenome. We identified through genome-scale CRISPR screening that MOZ and Menin-MLL chromatin regulatory complexes are cooperative and unique dependencies in GIST. These complexes were enriched at GIST-relevant genes and regulated their transcription. Inhibition of MOZ and Menin-MLL complexes decreased GIST cell proliferation by disrupting interactions with transcriptional/chromatin regulators, such as DOT1L. MOZ and Menin inhibition caused significant reductions in tumor burden in vivo, with superior effects observed with combined Menin and KIT inhibition. These results define unique chromatin regulatory dependencies in GIST and identify potential therapeutic strategies for clinical application.
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