例如："lncRNA", "apoptosis", "WRKY"

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

Leukemia. 2021 Jan;35(1):90-106. Epub 2020 Apr 02
Laura Godfrey 1 , Nicholas T Crump 1 , Sorcha O'Byrne 2 , I-Jun Lau 1 , Siobhan Rice 1 , Joe R Harman 1 , Thomas Jackson 2 , Natalina Elliott 2 , Gemma Buck 2 , Christopher Connor 3 , Ross Thorne 1 , David J H F Knapp 4 , Olaf Heidenreich 5 , Paresh Vyas 6 , Pablo Menendez 7 , Sarah Inglott 3 , Philip Ancliff 3 , Huimin Geng 8 , Irene Roberts 2 , Anindita Roy 9 , Thomas A Milne 10
Laura Godfrey 1 , Nicholas T Crump 1 , Sorcha O'Byrne 2 , I-Jun Lau 1 , Siobhan Rice 1 , Joe R Harman 1 , Thomas Jackson 2 , Natalina Elliott 2 , Gemma Buck 2 , Christopher Connor 3 , Ross Thorne 1 , David J H F Knapp 4 , Olaf Heidenreich 5 , Paresh Vyas 6 , Pablo Menendez 7 , Sarah Inglott 3 , Philip Ancliff 3 , Huimin Geng 8 , Irene Roberts 2 , Anindita Roy 9 , Thomas A Milne 10
+ et al

[No authors listed]

Author information
  • 1 MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • 2 Department of Paediatrics, University of Oxford, Oxford, UK.
  • 3 Great Ormond Street Hospital for Children, London, UK.
  • 4 MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • 5 Wolfson Childhood Cancer Research Centre, Newcastle University, Newcastle upon Tyne, UK.
  • 6 Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
  • 7 Centro de Investigación Biomédica en Red en cancer (CIBERONC)-ISCIII, Barcelona, Spain.
  • 8 Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA.
  • 9 Department of Paediatrics, University of Oxford, Oxford, UK. anindita.roy@paediatrics.ox.ac.uk.
  • 10 MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. thomas.milne@imm.ox.ac.uk.

摘要

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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