Abstract
Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found in a subset of benign and malignant cartilage tumors, gliomas and leukaemias. The mutant enzyme causes the production of D-2-hydroxyglutarate (D-2-HG), affecting CpG island and histone methylation. While mutations in IDH1/2 are early events in benign cartilage tumors, we evaluated whether these mutations play a role in malignant chondrosarcomas. Compared to IDH1/2 wildtype cell lines, chondrosarcoma cell lines harboring an endogenous IDH1 (n=3) or IDH2 mutation (n=2) showed up to a 100-fold increase in intracellular and extracellular D-2-HG levels. Specific inhibition of mutant IDH1 using AGI-5198 decreased levels of D-2-HG in a dose dependent manner. After 72 hours of treatment one out of three mutant IDH1 cell lines showed a moderate decrease in viability , while D-2-HG levels decreased >90%. Likewise, prolonged treatment (up to 20 passages) did not affect proliferation and migration. Furthermore, global gene expression, CpG island methylation as well as histone H3K4, -9, and -27 trimethylation levels remained unchanged. Thus, while IDH1/2 mutations cause enchondroma, malignant progression towards central chondrosarcoma renders chondrosarcoma growth independent of these mutations. Thus, monotherapy based on inhibition of mutant IDH1 appears insufficient for treatment of inoperable or metastasized chondrosarcoma patients.
Highlights
Mutations in isocitrate dehydrogenase 1 and -2 (IDH1 and -2) genes are found in acute myeloid leukemia (~20%) [1], gliomas (60-80%) [2, 3], cholangiocarcinomas (7-28%) [4,5,6] and in benign and malignant cartilage tumors [7,8,9,10]
Glioma and leukemia cells harboring mutations in IDH1 or -2 cannot be maintained in culture, we previously reported that chondrosarcoma cell lines retain these mutations [31] providing us with a model to functionally study the effects of IDH1 or -2 mutations in their naturally occurring context and to evaluate whether inhibition of mutant IDH1/2 could be a potential treatment strategy
The high prevalence of IDH1 or -2 mutations in enchondroma and chondrosarcoma, suggesting a causal rather than a bystander role in tumorigenesis, led us to investigate the function of these mutations in chondrosarcoma
Summary
Mutations in isocitrate dehydrogenase 1 and -2 (IDH1 and -2) genes are found in acute myeloid leukemia (~20%) [1], gliomas (60-80%) [2, 3], cholangiocarcinomas (7-28%) [4,5,6] and in benign and malignant cartilage tumors [7,8,9,10]. Enchondromas occur mostly solitary, while multiple enchondromas can be found in the non-hereditary Ollier disease or Maffucci syndrome [11, 12]. These syndromes are caused by somatic mosaic mutations in IDH1 or -2. Malignant progression towards secondary central chondrosarcoma occurs in ~1% of solitary enchondromas and up to ~50% in patients with multiple enchondromas [13]. Central conventional chondrosarcomas carry mutations in IDH1/2 in 38-70%
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