| First Author | Zhu Q | Year | 2019 |
| Journal | Cell Rep | Volume | 26 |
| Issue | 2 | Pages | 415-428.e5 |
| PubMed ID | 30625324 | Mgi Jnum | J:290877 |
| Mgi Id | MGI:6432009 | Doi | 10.1016/j.celrep.2018.12.059 |
| Citation | Zhu Q, et al. (2019) The Wnt-Driven Mll1 Epigenome Regulates Salivary Gland and Head and Neck Cancer. Cell Rep 26(2):415-428.e5 |
| abstractText | 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 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. |
