H3K79me2/3 controls enhancer-promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

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 th...

ver descrição completa

Detalhes bibliográficos
Autores: Godfrey, Laura|||0000-0002-6222-3563, Crump, Nicholas|||0000-0001-9610-6763, O'Byrne, Sorcha|||0000-0002-3116-1646, Lau, I. Jun, Rice, Siobhan, Harman, Joe R., Jackson, Thomas, Elliott, Natalina|||0000-0002-6713-7349, Buck, Gemma, Connor, Christopher, Thorne, Ross, Knapp, David J. H. F., Heidenreich, Olaf|||0000-0001-5404-6483, Vyas, Paresh, Menéndez Bujan, Pablo|||0000-0001-9372-1007, Inglott, Sara, Ancliff, Philip, Geng, Huimin, Roberts, Irene|||0000-0002-6094-6397, Roy, Anindita, Milne, Thomas|||0000-0002-0413-4271
Formato: artículo
Fecha de publicación:2021
País:España
Recursos:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:236076
Acesso em linha:https://ddd.uab.cat/record/236076
https://dx.doi.org/urn:doi:10.1038/s41375-020-0808-y
Access Level:acceso abierto
Palavra-chave:Acute lymphocytic leukaemia
Cancer genomics
Descrição
Resumo: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.

Registos relacionados