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

Authors
  • Godfrey, Laura1
  • Crump, Nicholas T1
  • O'Byrne, Sorcha2
  • Lau, I-Jun1
  • Rice, Siobhan1
  • Harman, Joe R1
  • Jackson, Thomas2
  • Elliott, Natalina2
  • Buck, Gemma2
  • Connor, Christopher3
  • Thorne, Ross1
  • Knapp, David J H F4
  • Heidenreich, Olaf5, 6
  • Vyas, Paresh1, 7
  • Menendez, Pablo8, 9, 10
  • Inglott, Sarah3
  • Ancliff, Philip3
  • Geng, Huimin11
  • Roberts, Irene1, 2
  • Roy, Anindita12
  • And 1 more
  • 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 Princess Maxima Centrum for Pediatric Oncology, Utrecht, The Netherlands. , (Netherlands)
  • 6 Wolfson Childhood Cancer Research Centre, Newcastle University, Newcastle upon Tyne, UK.
  • 7 Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
  • 8 Josep Carreras Leukemia Research Institute, Barcelona, Spain. , (Spain)
  • 9 Institucio Catalana of Recerca i Estudis Avançats (ICREA), Barcelona, Spain. , (Spain)
  • 10 Centro de Investigación Biomédica en Red en cancer (CIBERONC)-ISCIII, Barcelona, Spain. , (Spain)
  • 11 Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA.
  • 12 Department of Paediatrics, University of Oxford, Oxford, UK. [email protected]
  • 13 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. [email protected]
Type
Published Article
Journal
Leukemia
Publisher
Springer Nature
Publication Date
Jan 01, 2021
Volume
35
Issue
1
Pages
90–106
Identifiers
DOI: 10.1038/s41375-020-0808-y
PMID: 32242051
Source
Medline
Language
English
License
Unknown

Abstract

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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