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

Laura Godfrey, Nicholas T Crump, Sorcha O'Byrne, I-Jun Lau, Siobhan Rice, Joe R Harman, Thomas Jackson, Natalina Elliott, Gemma Buck, Christopher Connor, Ross Thorne, David J H F Knapp, Olaf Heidenreich, Paresh Vyas, Pablo Menendez, Sarah Inglott, Philip Ancliff, Huimin Geng, Irene Roberts, Anindita RoyThomas A Milne

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)90-106
Number of pages17
JournalLeukemia
Volume35
Issue number1
DOIs
Publication statusPublished - Jan 2021

Keywords

  • AC133 Antigen/genetics
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic/genetics
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Leukemic
  • Gene Silencing
  • Histones/metabolism
  • Humans
  • Immunophenotyping
  • Leukemia/genetics
  • Models, Biological
  • Myeloid-Lymphoid Leukemia Protein/genetics
  • Neoplastic Stem Cells/metabolism
  • Oncogene Proteins, Fusion/genetics
  • Promoter Regions, Genetic
  • Protein Binding

Fingerprint

Dive into the research topics of 'H3K79me2/3 controls enhancer-promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells'. Together they form a unique fingerprint.

Cite this