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The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2\/3). One key MLL-AF4 target gene is <jats:italic>PROM1<\/jats:italic>, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant <jats:italic>PROM1<\/jats:italic>\/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2\/3 enhancer element (KEE) leading to increased enhancer\u2013promoter interactions between <jats:italic>PROM1<\/jats:italic> and the nearby gene <jats:italic>TAPT1<\/jats:italic>. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in <jats:italic>PROM1<\/jats:italic>\/CD133 non-expressing cells, the <jats:italic>PROM1<\/jats:italic> locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of <jats:italic>TAPT1<\/jats:italic>, partially due to loss of interactions with the <jats:italic>PROM1<\/jats:italic> locus. Together, these results provide the first detailed analysis of <jats:italic>PROM1<\/jats:italic>\/CD133 regulation that explains CD133 expression in MLLr ALL.<\/jats:p>","DOI":"10.1038\/s41375-020-0808-y","type":"journal-article","created":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T10:04:16Z","timestamp":1585821856000},"page":"90-106","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["H3K79me2\/3 controls enhancer\u2013promoter interactions and activation of the pan-cancer stem cell marker PROM1\/CD133 in MLL-AF4 leukemia cells"],"prefix":"10.1038","volume":"35","author":[{"given":"Laura","family":"Godfrey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9610-6763","authenticated-orcid":false,"given":"Nicholas T.","family":"Crump","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sorcha","family":"O\u2019Byrne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Jun","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siobhan","family":"Rice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe R.","family":"Harman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalina","family":"Elliott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Buck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Connor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Thorne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J. 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