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

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. : 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. Keywords: tumor-propagating cells, epigenetics, solid tumors, ChIP-seq, H3K4me3 at promoters, SET domain, Axin