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The Wnt-Driven Mll1 Epigenome Regulates Salivary Gland and Head and Neck Cancer

We identified a regulatory system that acts downstream of Wnt/β-catenin signaling in salivary gland and head and neck carcinomas. We show in a mouse tumor model of K14-Cre-induced Wnt/β-catenin gain-of-function and Bmpr1a loss-of-function mutations that tumor-propagating cells exhibit increased Mll1...

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Published in:Cell reports (Cambridge) 2019-01, Vol.26 (2), p.415-428.e5
Main Authors: Zhu, Qionghua, Fang, Liang, Heuberger, Julian, Kranz, Andrea, Schipper, Jörg, Scheckenbach, Kathrin, Vidal, Ramon Oliveira, Sunaga-Franze, Daniele Yumi, Müller, Marion, Wulf-Goldenberg, Annika, Sauer, Sascha, Birchmeier, Walter
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Language:English
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Summary:We identified a regulatory system that acts downstream of Wnt/β-catenin signaling in salivary gland and head and neck carcinomas. We show in a mouse tumor model of K14-Cre-induced Wnt/β-catenin gain-of-function and Bmpr1a loss-of-function mutations that tumor-propagating cells exhibit increased Mll1 activity and genome-wide increased H3K4 tri-methylation at promoters. Null mutations of Mll1 in tumor mice and in xenotransplanted human head and neck tumors resulted in loss of self-renewal of tumor-propagating cells and in block of tumor formation but did not alter normal tissue homeostasis. CRISPR/Cas9 mutagenesis and pharmacological interference of Mll1 at sequences that inhibit essential protein-protein interactions or the SET enzyme active site also blocked the self-renewal of mouse and human tumor-propagating cells. Our work provides strong genetic evidence for a crucial role of Mll1 in solid tumors. Moreover, inhibitors targeting specific Mll1 interactions might offer additional directions for therapies to treat these aggressive tumors. [Display omitted] •High Wnt/β-catenin and Mll1 are linked to high H3K4me3 at promoters in mouse tumors•Mll1 is required for the initiation and maintenance of salivary gland tumors•SET domain mutations of Mll1 reduce the self-renewal of tumor-propagating cells•Genetic Mll1 ablation reduces tumor initiation of human head and neck cancer cells Mutations of Mll1 genes were described in leukemia, but little is known about the roles of Mll1 in solid tumors. Zhu et al. provide genetic evidence for a crucial role of Mll1 in Wnt/β-catenin-driven salivary gland and head and neck cancers.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2018.12.059