TY - JOUR
T1 - Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML)
AU - Steinhäuser, Sophie
AU - Silva, Patricia
AU - Lenk, Lennart
AU - Beder, Thomas
AU - Hartmann, Alina
AU - Hänzelmann, Sonja
AU - Fransecky, Lars
AU - Neumann, Martin
AU - Bastian, Lorenz
AU - Lipinski, Simone
AU - Richter, Kathrin
AU - Bultmann, Miriam
AU - Hübner, Emely
AU - Xia, Shuli
AU - Röllig, Christoph
AU - Vogiatzi, Fotini
AU - Schewe, Denis Martin
AU - Yumiceba, Veronica
AU - Schultz, Kristin
AU - Spielmann, Malte
AU - Baldus, Claudia Dorothea
N1 - Funding Information:
Here we show that upregulation of tyrosine kinase PDGFRA is associated with altered 3D DNA conformation in IDH1-mut AML and therefore may represent a novel therapeutic target in IDH1-mut AML. PDGFRA is involved in cell proliferation, migration and invasion, cell survival and chemotaxis []. In the Network of Cancer Genes (NGC) project it has also been classified as driver gene with oncogenic potential and its overexpression has been reported in breast cancer, ovarian cancer and thyroid cancer [–]. Yet, activation of PDGFRA expression in connection with altered DNA conformation as potential leukemogenic mechanism in IDH1-mut AML has not been suggested. We provide evidence for decreased CTCF binding at the CTCF-anchor region upstream of PDGFRA due to increased DNA methylation, suggesting disrupted DNA loop formation and insulation and subsequent upregulation of PDGFRA expression. Upregulated PDGFRA-CTCF methylation and PDGFRA expression was also confirmed upon exogenous treatment with 2-HG, confirming 2-HG mediated CTCF hypermethylation as mechanism of action upregulating PDGFRA. This finding is supported by the work from the B. Bernstein research group showing disrupted DNA looping and subsequent activation of PDGFRA expression in IDH1-mut glioma []. Our finding of upregulated PDGFRA expression in connection with altered DNA looping in IDH1-mut AML now extends this mechanism of action beyond the context of glioma. As observed in clinical data of IDH1-mut AML patients, IDH1-mut glioma patients with high PDGFRA expression also showed significantly worse survival rates, supporting a strong clinical relevance of this mechanism. These data strengthen the hypothesis that the correlation between IDH1 mutation-dependent DNA conformational changes and upregulated PDGFRA expression may be a more global mechanism across different cancer types.
Funding Information:
We would like to thank Gabriele Riesen for the great help during the in vivo experiments included in this study. Furthermore, we would like to thank SX (Kennedy Krieger Institute Baltimore) for kindly providing the IDH1 p.R132H sgRNA plasmid for CRISPR base editing. This project was funded by the Deutsche José Carreras Leukämie Stiftung (DJCLS).
Publisher Copyright:
© 2022, The Author(s).
PY - 2023/1
Y1 - 2023/1
N2 - 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. [Figure not available: see fulltext.].
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. [Figure not available: see fulltext.].
UR - http://www.scopus.com/inward/record.url?scp=85142291328&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85142291328&partnerID=8YFLogxK
U2 - 10.1038/s41375-022-01751-6
DO - 10.1038/s41375-022-01751-6
M3 - Article
C2 - 36411356
AN - SCOPUS:85142291328
SN - 0887-6924
VL - 37
SP - 134
EP - 142
JO - Leukemia
JF - Leukemia
IS - 1
ER -