학술논문
Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRAactivation due to insulator disruption in acute myeloid leukemia (AML)
Document Type
Article
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
Source
Leukemia; January 2023, Vol. 37 Issue: 1 p134-142, 9p
Subject
Language
ISSN
08876924; 14765551
Abstract
Acute myeloid leukemia (AML) is characterized by complex molecular alterations and driver mutations. Elderly patients show increased frequencies of IDHmutations with high chemoresistance and relapse rates despite recent therapeutic advances. Besides being associated with global promoter hypermethylation, IDH1mutation 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 IDH1p.R132H mutation in altering 3D DNA-architecture and subsequent oncogene activation in AML. Using public RNA-Seq data, we identified upregulation of tyrosine kinase PDGFRAin IDH1-mutant patients, correlating with poor prognosis. DNA methylation analysis identified CpG hypermethylation within a CTCF-anchor upstream of PDGFRAin IDH1-mutant patients. Increased PDGFRAexpression, PDGFRA-CTCF methylation and decreased CTCF binding were confirmed in AML CRISPR cells with heterozygous IDH1p.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 IDH1p.R132H mutation leads to CTCF hypermethylation, disrupting DNA-looping and insulation of PDGFRA, resulting in PDGFRAupregulation in IDH1-mutant AML. Treatment with dasatinib may offer a novel treatment strategy for IDH1-mutant AML.