Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT Inhibitor Decitabine.
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Sevin Turcan1,*, Armida W. M. Fabius1,*, Alexandra Borodovsky2, Alicia Pedraza1, Cameron Brennan1, Jason Huse1, Agnes Viale3, Gregory J. Riggins2, and Timothy A. Chan1,4,5
1 Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
2 Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD.
3 Genomics Core, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
4 Dept. of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
5 Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
* These authors contributed equally to this work
Timothy A. Chan, email:
Keywords: glioma, isocitrate dehydrogenase, methylation, epigenetics, treatment
Received: September 12, 2013 Accepted: September 16, 2013 Published: September 16, 2013
Mutation in the IDH1 or IDH2 genes occurs frequently in gliomas and other human malignancies. In intermediate grade gliomas, IDH1 mutation is found in over 70% of tumors. These mutations impart the mutant IDH enzyme with a neomorphic activity – the ability to synthesize 2-hydroxyglutarate (2-HG). This ability leads to a reprogramming of chromatin state, a block in differentiation, and the establishment of the glioma hypermethylator phenotype (G-CIMP). It has been hypothesized but not proven that the extensive DNA methylation that occurs in G-CIMP tumors helps maintain and “lock in” glioma cancer cells in a dedifferentiated state. Here, we tested this hypothesis by treating patient derived IDH1 mutant glioma initiating cells (GIC) with non-cytotoxic, epigenetically targeted doses of the DNMT inhibitor decitabine. Global methylome analysis of treated IDH1 mutant GICs showed that DAC treatment resulted in reversal of DNA methylation marks induced by IDH and the re-expression of genes associated with differentiation. Accordingly, treatment of IDH1 mutant glioma cells resulted in a dramatic loss of stem-like properties and efficient adoption of markers of differentiation, effects not seen in decitabine treated IDH wild-type GICs. Induction of differentiation was much more efficient than that seen following treatment with a specific inhibitor of mutant IDH enzyme (Agios). Decitabine also decreased replicative potential and tumor growth in vivo. Reexpression of polycomb regulated genes accompanied these DAC-induced phenotypes. In total, our data indicates that targeting the pathologic DNA methylation in IDH mutant cells can reverse mutant IDH induced hypermethylation and block in differentiation and promote tumor control. These findings have substantial impact for exploring new treatment strategies for patients with IDH mutant gliomas.
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