PT Journal
AU Steinhäuser, S
   Silva, P
   Lenk, L
   Beder, T
   Hartmann, A
   Hänzelmann, S
   Fransecky, L
   Neumann, M
   Bastian, L
   Lipinski, S
   Richter, K
   Bultmann, M
   Hübner, E
   Xia, S
   Röllig, C
   Vogiatzi, F
   Schewe, DM
   Yumiceba, V
   Schultz, K
   Spielmann, M
   Baldus, CD
TI Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML)
SO Leukemia : the journal of normal and malignant hemopoiese ; official journal of the Leukemia Research Fund U.K.
JI Leukemia
PY 2023
BP 134
EP 142
VL 37
IS 1
PU Springer Science and Business Media LLC
DI 10.1038/s41375-022-01751-6
WP https://macau.uni-kiel.de/receive/macau_mods_00004516
LA en
DE Humans; Isocitrate Dehydrogenase; Mutation; Oncogenes; Aged; Leukemia, Myeloid, Acute; Carcinogenesis; Dasatinib
SN 0887-6924
AB 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.
PI London; Baltimore, Md.; Basingstoke
ER