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

We identified a regulatory system that acts downstream of Wnt/beta-catenin signaling in salivary gland and head and neck carcinomas. We show in a mouse tumor model of K14-Cre-induced Wnt/beta-catenin gain-of-function and Bmpr1a loss-of-function mutations that tumor-propagating cells exhibit increased Mill activity and genome-wide increased H3K4 trimethylation 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 Mill 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 Mill in solid tumors. Moreover, inhibitors targeting specific Mill interactions might offer additional directions for therapies to treat these aggressive tumors.