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Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML)
Acute myeloid leukemia (AML) is characterized by complex molecular alterations and driver mutations. Elderly patients show increased frequencies of IDH mutations with high chemoresistance and relapse rates despite recent therapeutic advances. Besides being associated with global promoter hypermethyl...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9883162/ https://www.ncbi.nlm.nih.gov/pubmed/36411356 http://dx.doi.org/10.1038/s41375-022-01751-6 |
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author | Steinhäuser, Sophie Silva, Patricia Lenk, Lennart Beder, Thomas Hartmann, Alina Hänzelmann, Sonja Fransecky, Lars Neumann, Martin Bastian, Lorenz Lipinski, Simone Richter, Kathrin Bultmann, Miriam Hübner, Emely Xia, Shuli Röllig, Christoph Vogiatzi, Fotini Schewe, Denis Martin Yumiceba, Veronica Schultz, Kristin Spielmann, Malte Baldus, Claudia Dorothea |
author_facet | Steinhäuser, Sophie Silva, Patricia Lenk, Lennart Beder, Thomas Hartmann, Alina Hänzelmann, Sonja Fransecky, Lars Neumann, Martin Bastian, Lorenz Lipinski, Simone Richter, Kathrin Bultmann, Miriam Hübner, Emely Xia, Shuli Röllig, Christoph Vogiatzi, Fotini Schewe, Denis Martin Yumiceba, Veronica Schultz, Kristin Spielmann, Malte Baldus, Claudia Dorothea |
author_sort | Steinhäuser, Sophie |
collection | PubMed |
description | Acute myeloid leukemia (AML) is characterized by complex molecular alterations and driver mutations. Elderly patients show increased frequencies of IDH mutations with high chemoresistance and relapse rates despite recent therapeutic advances. Besides being associated with global promoter hypermethylation, IDH1 mutation facilitated changes in 3D DNA-conformation by CTCF-anchor methylation and upregulated oncogene expression in glioma, correlating with poor prognosis. Here, we investigated the role of IDH1 p.R132H mutation in altering 3D DNA-architecture and subsequent oncogene activation in AML. Using public RNA-Seq data, we identified upregulation of tyrosine kinase PDGFRA in IDH1-mutant patients, correlating with poor prognosis. DNA methylation analysis identified CpG hypermethylation within a CTCF-anchor upstream of PDGFRA in IDH1-mutant patients. Increased PDGFRA expression, PDGFRA-CTCF methylation and decreased CTCF binding were confirmed in AML CRISPR cells with heterozygous IDH1 p.R132H mutation and upon exogenous 2-HG treatment. IDH1-mutant cells showed higher sensitivity to tyrosine kinase inhibitor dasatinib, which was supported by reduced blast count in a patient with refractory IDH1-mutant AML after dasatinib treatment. Our data illustrate that IDH1 p.R132H mutation leads to CTCF hypermethylation, disrupting DNA-looping and insulation of PDGFRA, resulting in PDGFRA upregulation in IDH1-mutant AML. Treatment with dasatinib may offer a novel treatment strategy for IDH1-mutant AML. [Image: see text] |
format | Online Article Text |
id | pubmed-9883162 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98831622023-01-29 Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML) Steinhäuser, Sophie Silva, Patricia Lenk, Lennart Beder, Thomas Hartmann, Alina Hänzelmann, Sonja Fransecky, Lars Neumann, Martin Bastian, Lorenz Lipinski, Simone Richter, Kathrin Bultmann, Miriam Hübner, Emely Xia, Shuli Röllig, Christoph Vogiatzi, Fotini Schewe, Denis Martin Yumiceba, Veronica Schultz, Kristin Spielmann, Malte Baldus, Claudia Dorothea Leukemia Article Acute myeloid leukemia (AML) is characterized by complex molecular alterations and driver mutations. Elderly patients show increased frequencies of IDH mutations with high chemoresistance and relapse rates despite recent therapeutic advances. Besides being associated with global promoter hypermethylation, IDH1 mutation facilitated changes in 3D DNA-conformation by CTCF-anchor methylation and upregulated oncogene expression in glioma, correlating with poor prognosis. Here, we investigated the role of IDH1 p.R132H mutation in altering 3D DNA-architecture and subsequent oncogene activation in AML. Using public RNA-Seq data, we identified upregulation of tyrosine kinase PDGFRA in IDH1-mutant patients, correlating with poor prognosis. DNA methylation analysis identified CpG hypermethylation within a CTCF-anchor upstream of PDGFRA in IDH1-mutant patients. Increased PDGFRA expression, PDGFRA-CTCF methylation and decreased CTCF binding were confirmed in AML CRISPR cells with heterozygous IDH1 p.R132H mutation and upon exogenous 2-HG treatment. IDH1-mutant cells showed higher sensitivity to tyrosine kinase inhibitor dasatinib, which was supported by reduced blast count in a patient with refractory IDH1-mutant AML after dasatinib treatment. Our data illustrate that IDH1 p.R132H mutation leads to CTCF hypermethylation, disrupting DNA-looping and insulation of PDGFRA, resulting in PDGFRA upregulation in IDH1-mutant AML. Treatment with dasatinib may offer a novel treatment strategy for IDH1-mutant AML. [Image: see text] Nature Publishing Group UK 2022-11-21 2023 /pmc/articles/PMC9883162/ /pubmed/36411356 http://dx.doi.org/10.1038/s41375-022-01751-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Steinhäuser, Sophie Silva, Patricia Lenk, Lennart Beder, Thomas Hartmann, Alina Hänzelmann, Sonja Fransecky, Lars Neumann, Martin Bastian, Lorenz Lipinski, Simone Richter, Kathrin Bultmann, Miriam Hübner, Emely Xia, Shuli Röllig, Christoph Vogiatzi, Fotini Schewe, Denis Martin Yumiceba, Veronica Schultz, Kristin Spielmann, Malte Baldus, Claudia Dorothea Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML) |
title | Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML) |
title_full | Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML) |
title_fullStr | Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML) |
title_full_unstemmed | Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML) |
title_short | Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML) |
title_sort | isocitrate dehydrogenase 1 mutation drives leukemogenesis by pdgfra activation due to insulator disruption in acute myeloid leukemia (aml) |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9883162/ https://www.ncbi.nlm.nih.gov/pubmed/36411356 http://dx.doi.org/10.1038/s41375-022-01751-6 |
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