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