000K  utf8
1100  $c2023
1500  eng
2050  urn:nbn:de:gbv:8:3-2024-00235-3
2051  10.1038/s41375-022-01751-6
3000  Steinhäuser, Sophie
3010  Baldus, Claudia Dorothea
3010  Bastian, Lorenz
3010  Beder, Thomas
3010  Bultmann, Miriam
3010  Fransecky, Lars
3010  Hänzelmann, Sonja
3010  Hartmann, Alina
3010  Hübner, Emely
3010  Lenk, Lennart
3010  Lipinski, Simone
3010  Neumann, Martin
3010  Richter, Kathrin
3010  Röllig, Christoph
3010  Schewe, Denis Martin
3010  Schultz, Kristin
3010  Silva, Patricia
3010  Spielmann, Malte
3010  Vogiatzi, Fotini
3010  Xia, Shuli
3010  Yumiceba, Veronica
4000  Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML)$hSpringer Science and Business Media LLC  [Steinhäuser, Sophie]
4030  $nSpringer Science and Business Media LLC
4209  Acute myeloid leukemia (AML) is characterized by complex molecular alterations and driver mutations. Elderly patients show increased frequencies of IDH mutations with high chemoresistance and relapse rates despite recent therapeutic advances. Besides being associated with global promoter hypermethylation, IDH1 mutation facilitated changes in 3D DNA-conformation by CTCF-anchor methylation and upregulated oncogene expression in glioma, correlating with poor prognosis. Here, we investigated the role of IDH1 p.R132H mutation in altering 3D DNA-architecture and subsequent oncogene activation in AML. Using public RNA-Seq data, we identified upregulation of tyrosine kinase PDGFRA in IDH1-mutant patients, correlating with poor prognosis. DNA methylation analysis identified CpG hypermethylation within a CTCF-anchor upstream of PDGFRA in IDH1-mutant patients. Increased PDGFRA expression, PDGFRA-CTCF methylation and decreased CTCF binding were confirmed in AML CRISPR cells with heterozygous IDH1 p.R132H mutation and upon exogenous 2-HG treatment. IDH1-mutant cells showed higher sensitivity to tyrosine kinase inhibitor dasatinib, which was supported by reduced blast count in a patient with refractory IDH1-mutant AML after dasatinib treatment. Our data illustrate that IDH1 p.R132H mutation leads to CTCF hypermethylation, disrupting DNA-looping and insulation of PDGFRA, resulting in PDGFRA upregulation in IDH1-mutant AML. Treatment with dasatinib may offer a novel treatment strategy for IDH1-mutant AML.
4950  https://doi.org/10.1038/s41375-022-01751-6$xR$3Volltext$534
4950  https://nbn-resolving.org/urn:nbn:de:gbv:8:3-2024-00235-3$xR$3Volltext$534
4961  https://macau.uni-kiel.de/receive/macau_mods_00004516
5051  610
5550  Aged
5550  Carcinogenesis
5550  Dasatinib
5550  Humans
5550  Isocitrate Dehydrogenase
5550  Leukemia, Myeloid, Acute
5550  Mutation
5550  Oncogenes