Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML)

• DOI: 10.1038/s41375-022-01751-6
• Publication Date: 2022-11-21T09:06:16Z
• Authors: Sophie Steinhäuser; Patricia Silva; Lennart Lenk; Thomas Beder; Alina Hartmann; Sonja Hänzelmann; Lars Fransecky; Martin Neumann; Lorenz Bastian; Simone Lipinski; Kathrin Richter; Miriam Bultmann; Emely Hübner; Shuli Xia; Christoph Röllig; Fotini Vogiatzi; Denis Martin Schewe; Veronica Yumiceba; Kristin Schultz; Malte Spielmann; Claudia Dorothea ...
• Keywords: PDGFRA; Isocitrate dehydrogenase

Acute myeloid leukemia (AML) is characterized by complex molecular alterations and driver mutations. Elderly patients show increased frequencies of IDH mutations with high chemoresistance relapse rates despite recent therapeutic advances. Besides being associated global promoter hypermethylation, IDH1 mutation facilitated changes in 3D DNA-conformation CTCF-anchor methylation upregulated oncogene expression glioma, correlating poor prognosis. Here, we investigated the role p.R132H altering DNA-architecture subsequent activation AML. Using public RNA-Seq data, identified upregulation tyrosine kinase PDGFRA IDH1-mutant patients, DNA analysis CpG hypermethylation within a upstream patients. Increased expression, PDGFRA-CTCF decreased CTCF binding were confirmed AML CRISPR cells heterozygous upon exogenous 2-HG treatment. showed higher sensitivity to inhibitor dasatinib, which was supported reduced blast count patient refractory after dasatinib Our data illustrate that leads disrupting DNA-looping insulation PDGFRA, resulting Treatment may offer novel treatment strategy for