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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,12,10]]},"abstract":"<jats:p>The oncoprotein transcription factor MYC is overexpressed in the majority of cancers. Key to its oncogenic activity is the ability of MYC to regulate gene expression patterns that drive and maintain the malignant state. MYC is also considered a validated anticancer target, but efforts to pharmacologically inhibit MYC have failed. The dependence of MYC on cofactors creates opportunities for therapeutic intervention, but for any cofactor this requires structural understanding of how the cofactor interacts with MYC, knowledge of the role it plays in MYC function, and demonstration that disrupting the cofactor interaction will cause existing cancers to regress. One cofactor for which structural information is available is WDR5, which interacts with MYC to facilitate its recruitment to chromatin. To explore whether disruption of the MYC\u2013WDR5 interaction could potentially become a viable anticancer strategy, we developed a Burkitt's lymphoma system that allows replacement of wild-type MYC for mutants that are defective for WDR5 binding or all known nuclear MYC functions. Using this system, we show that WDR5 recruits MYC to chromatin to control the expression of genes linked to biomass accumulation. We further show that disrupting the MYC\u2013WDR5 interaction within the context of an existing cancer promotes rapid and comprehensive tumor regression in vivo. These observations connect WDR5 to a core tumorigenic function of MYC and establish that, if a therapeutic window can be established, MYC\u2013WDR5 inhibitors could be developed as anticancer agents.<\/jats:p>","DOI":"10.1073\/pnas.1910391116","type":"journal-article","created":{"date-parts":[[2019,11,25]],"date-time":"2019-11-25T20:29:29Z","timestamp":1574713769000},"page":"25260-25268","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":121,"title":["Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance"],"prefix":"10.1073","volume":"116","author":[{"given":"Lance R.","family":"Thomas","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare M.","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April M.","family":"Weissmiller","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Creighton","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelly L.","family":"Lorey","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen W.","family":"Fesik","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine M.","family":"Eischen","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William P.","family":"Tansey","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,11,25]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/757534","article-title":"Mammalian MYC proteins and cancer","volume":"2013","author":"Tansey W. 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