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4 results on '"Ancliff, P"'

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

Author

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

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Oncology and Carcinogenesis, Orphan Drug, Hematology, Pediatric Cancer, Stem Cell Research - Nonembryonic - Non-Human, Rare Diseases, Stem Cell Research, Cancer, Pediatric, Genetics, Aetiology, 2.1 Biological and endogenous factors, AC133 Antigen, Biomarkers, Tumor, Cell Line, Tumor, Cell Transformation, Neoplastic, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, Gene Silencing, Histones, Humans, Immunophenotyping, Leukemia, Models, Biological, Myeloid-Lymphoid Leukemia Protein, Neoplastic Stem Cells, Oncogene Proteins, Fusion, Promoter Regions, Genetic, Protein Binding, Immunology, Cardiovascular medicine and haematology, Clinical sciences, Oncology and carcinogenesis
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.

Published
2021

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

Author

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., and Universitat Autònoma de Barcelona

Subjects
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
Abstract

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.

Published
2020

3. Targeting acute myeloid leukemia by drug-induced c-MYB degradation

Author

Walf-Vorderwülbecke, V, primary, Pearce, K, additional, Brooks, T, additional, Hubank, M, additional, van den Heuvel-Eibrink, M M, additional, Zwaan, C M, additional, Adams, S, additional, Edwards, D, additional, Bartram, J, additional, Samarasinghe, S, additional, Ancliff, P, additional, Khwaja, A, additional, Goulden, N, additional, Williams, G, additional, de Boer, J, additional, and Williams, O, additional

Published
2017
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4. Targeting acute myeloid leukemia by drug-induced c-MYB degradation

Author

Walf-Vorderwülbecke, V, Pearce, K, Brooks, T, Hubank, M, van den Heuvel-Eibrink, M M, Zwaan, C M, Adams, S, Edwards, D, Bartram, J, Samarasinghe, S, Ancliff, P, Khwaja, A, Goulden, N, Williams, G, de Boer, J, and Williams, O

Abstract

Despite advances in our understanding of the molecular basis for particular subtypes of acute myeloid leukemia (AML), effective therapy remains a challenge for many individuals suffering from this disease. A significant proportion of both pediatric and adult AML patients cannot be cured and since the upper limits of chemotherapy intensification have been reached, there is an urgent need for novel therapeutic approaches. The transcription factor c-MYB has been shown to play a central role in the development and progression of AML driven by several different oncogenes, including mixed lineage leukemia (MLL)-fusion genes. Here, we have used a c-MYB gene expression signature from MLL-rearranged AML to probe the Connectivity Map database and identified mebendazole as a c-MYB targeting drug. Mebendazole induces c-MYB degradation via the proteasome by interfering with the heat shock protein 70 (HSP70) chaperone system. Transient exposure to mebendazole is sufficient to inhibit colony formation by AML cells, but not normal cord blood-derived cells. Furthermore, mebendazole is effective at impairing AML progression in vivo in mouse xenotransplantation experiments. In the context of widespread human use of mebendazole, our data indicate that mebendazole-induced c-MYB degradation represents a safe and novel therapeutic approach for AML.

Published
2018
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