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

Autor: Godfrey, L., Crump, N. T., O'Byrne, S., Lau, I. J., Rice, S., Harman, J. R., Jackson, T., Elliott, N., Buck, G., Connor, C., Thorne, R., Knapp, D. J. H. F., Heidenreich, O., Vyas, P., Menéndez, Pablo, Inglott, S., Ancliff, P., Geng, H., Roberts, I., Roy, A., Milne, T. A., Universitat Autònoma de Barcelona
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Cancer Research
Oncogene Proteins
Fusion
Stem cell marker
Cell Transformation
Histones
Models
hemic and lymphatic diseases
Cancer genomics
2.1 Biological and endogenous factors
AC133 Antigen
Aetiology
Promoter Regions
Genetic
Cancer
Oncogene Proteins
Leukemic
Pediatric
Tumor
Leukemia
biology
Gene Expression Regulation
Leukemic
Hematology
Cell biology
Cell Transformation
Neoplastic
Enhancer Elements
Genetic
Oncology
Neoplastic Stem Cells
Stem Cell Research - Nonembryonic - Non-Human
Stem cell
PRC2
Myeloid-Lymphoid Leukemia Protein
Protein Binding
Enhancer Elements
Pediatric Cancer
Clinical Sciences
Oncology and Carcinogenesis
Immunology
Locus (genetics)
Models
Biological
Article
Cell Line
Immunophenotyping
Promoter Regions
Histone H3
Rare Diseases
Genetic
Cell Line
Tumor
Genetics
Biomarkers
Tumor
Humans
Gene Silencing
Enhancer
Fusion
Gene
neoplasms
Neoplastic
Acute lymphocytic leukaemia
DOT1L
Biological
Stem Cell Research
Orphan Drug
Gene Expression Regulation
biology.protein
Biomarkers
Zdroj: Leukemia
Leukemia, vol 35, iss 1
r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol
instname
Dipòsit Digital de Documents de la UAB
Universitat Autònoma de Barcelona
ISSN: 1476-5551
0887-6924
Popis: Altres ajuts: Acknowledgements TAM, LG, NTC, I-JL, RT, JRH, and SR were funded by Medical Research Council (MRC, UK) Molecular Haematology Unit grant MC_UU_12009/6, MC_UU_00016/6, and MR/ M003221/1. AR was supported by a Bloodwise Clinician Scientist Fellowship (grants: 14041 and 17001), Wellcome Trust Clinical Research Career Development Fellowship (216632/Z/19/Z), Lady Tata Memorial International Fellowship, and EHA-ASH Translational Research Training in Hematology Fellowship. SOB was funded by the Department of Paediatrics and Alexander Thatte Fund, University of Oxford. DJHFK is funded by a CIHR Postdoctoral Fellowship. IR is supported by the NIHR Oxford BRC, by a Bloodwise Program Grant (13001) and by the MRC Molecular Haematology Unit (MC_UU_12009/14). PV via the Molecular Haematology Unit (MC_UU_12009) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) Programme. We would like to acknowledge the WIMM Flow Cytometry Facility which is supported by the MRC HIU, MRC MHU (MC_UU_12009), NIHR Oxford BRC, Kay Kendall Leukemia Fund (KKL1057), John Fell Fund (131/030 and 101/517), the EPA fund (CF182 and CF170), and by the WIMM Strategic Alliance awards G0902418 and MC_UU_12025. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust Grant Reference 090532/Z/09/Z); the MRC WIMM Centre for Computational Biology (CCB), Radcliffe Department of Medicine, University of Oxford; and Jelena Telenius for the use of her pipelines. B-ALL work in PM's lab is financially supported by [...], the Fundación Uno entre Cienmil, the Fundación Leo Messi. PM also acknowledges structural support from the Obra Social La Caixa-Fundaciò Josep Carreras. The human fetal material was provided by the Joint MRC/ Wellcome Trust Grant 099175/Z/ 12/Z Human Developmental Biology Resource (http://hdbr.org). We gratefully acknowledge the kind generosity of patients, their parents, and staff at Great Ormond Street Hospital, London. 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.
Databáze: OpenAIRE
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