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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

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 th...

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Autores principales: 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 J. H. F., Heidenreich, Olaf, Vyas, Paresh, Menendez, Pablo, Inglott, Sarah, Ancliff, Philip, Geng, Huimin, Roberts, Irene, Roy, Anindita, Milne, Thomas A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787973/
https://www.ncbi.nlm.nih.gov/pubmed/32242051
http://dx.doi.org/10.1038/s41375-020-0808-y
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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 J. H. F.
Heidenreich, Olaf
Vyas, Paresh
Menendez, Pablo
Inglott, Sarah
Ancliff, Philip
Geng, Huimin
Roberts, Irene
Roy, Anindita
Milne, Thomas A.
author_facet 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 J. H. F.
Heidenreich, Olaf
Vyas, Paresh
Menendez, Pablo
Inglott, Sarah
Ancliff, Philip
Geng, Huimin
Roberts, Irene
Roy, Anindita
Milne, Thomas A.
author_sort Godfrey, Laura
collection PubMed
description 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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spelling pubmed-77879732021-01-11 H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells 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 J. H. F. Heidenreich, Olaf Vyas, Paresh Menendez, Pablo Inglott, Sarah Ancliff, Philip Geng, Huimin Roberts, Irene Roy, Anindita Milne, Thomas A. Leukemia Article 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. Nature Publishing Group UK 2020-04-02 2021 /pmc/articles/PMC7787973/ /pubmed/32242051 http://dx.doi.org/10.1038/s41375-020-0808-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
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 J. H. F.
Heidenreich, Olaf
Vyas, Paresh
Menendez, Pablo
Inglott, Sarah
Ancliff, Philip
Geng, Huimin
Roberts, Irene
Roy, Anindita
Milne, Thomas A.
H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells
title H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells
title_full H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells
title_fullStr H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells
title_full_unstemmed H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells
title_short H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells
title_sort h3k79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker prom1/cd133 in mll-af4 leukemia cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787973/
https://www.ncbi.nlm.nih.gov/pubmed/32242051
http://dx.doi.org/10.1038/s41375-020-0808-y
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