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Godfrey, Laura; Crump, Nicholas T; O'Byrne, Sorcha; Lau, I-Jun; Rice, Siobhan; Harman, Joe R; Jackson, Thomas; Elliott, Natalina; Buck, Gemma; Connor, Christopher; Thorne, Ross; Knapp, David J H F; Heidenreich, Olaf; Vyas, Paresh; Menendez, Pablo; Inglott, Sarah; Ancliff, Philip; Geng, Huimin; Roberts, Irene; Roy, Anindita; Milne, Thomas A
Leukemia, 01/2021, Volume: 35, Issue: 1Journal Article
MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. 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 PROM1, 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 PROM1/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-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.
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