Mutant IDH impairs chromatin binding by PDGFB to promote chromosome instability
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ABSTRACT:
PROVIDER: PRJNA1179968 | ENA |
REPOSITORIES: ENA
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Project description:Non-canonical roles for growth factors in the nucleus have been previously described, but their mechanism of action and biological roles remain enigmatic. Platelet-derived growth factor B (PDGFB) can drive formation of low-grade glioma and here we show that it localizes to the nucleus of human glioma cells where it binds chromatin to preserve genome stability and cell lineage. Failure of PDGFB to localize to the nucleus leads to chromosomal abnormalities, aberrant heterochromatin architecture and accelerated tumorigenesis. Furthermore, nuclear localization of PDGFB is reliant upon the expression levels and mutation status of isocitrate dehydrogenase (IDH). Unexpectedly, we identified macrophages as the predominant source of PDGFB in human, finding that immune-derived PDGFB can localize to the nucleus of glioma cells. Collectively, these studies show that immune derived PDGFB enters the nucleus of glioma cells to maintain genomic stability, while identifying a new mechanism by which IDH mutations promote gliomagenesis.
2024-11-10 | GSE280688 | GEO
Project description:Non-canonical roles for growth factors in the nucleus have been previously described, but their mechanism of action and biological roles remain enigmatic. Platelet-derived growth factor B (PDGFB) can drive formation of low-grade glioma and here we show that it localizes to the nucleus of human glioma cells where it binds chromatin to preserve genome stability and cell lineage. Failure of PDGFB to localize to the nucleus leads to chromosomal abnormalities, aberrant heterochromatin architecture and accelerated tumorigenesis. Furthermore, nuclear localization of PDGFB is reliant upon the expression levels and mutation status of isocitrate dehydrogenase (IDH). Unexpectedly, we identified macrophages as the predominant source of PDGFB in human, finding that immune-derived PDGFB can localize to the nucleus of glioma cells. Collectively, these studies show that immune derived PDGFB enters the nucleus of glioma cells to maintain genomic stability, while identifying a new mechanism by which IDH mutations promote gliomagenesis.
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Project description:Mutant IDH impairs chromatin binding by PDGFB to promote chromosome instability [scATAC-Seq]
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2020-06-22 | GSE113857 | GEO
Project description:Gene expression of mouse hepatoblasts (HBs) expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays that were processed at the Dana-Farber Cancer Institute core facility (http://macf-web.dfci.harvard.edu/) using their standard protocol. Mutations in Isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly primary liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alphaketoglutarate (aKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple aKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks primary liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF4a, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models (GEMMs) expressing mutant IDH in the adult liver show aberrant response to hepatic injury, characterized by HNF4a silencing, impaired hepatocyte differentiation and markedly elevated levels of cell proliferation. Moreover, mutant IDH and activated Kras, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis and present a novel GEMM of IDH-driven malignancy. Gene expression of HBs expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls under a doxycycline-inducible system (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays.
2014-04-30 | E-GEOD-57002 | biostudies-arrayexpress
Project description:Mutations in the genes encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a variety of tumor types, resulting in production of the proposed oncometabolite, 2-hydroxyglutarate (2-HG). How mutant IDH and 2-HG alter signaling pathways to promote cancer, though, remains unclear. Additionally, there exist relatively few cell lines with IDH mutations. To examine the effect of endogenous IDH mutations and 2-HG, we created a panel of isogenic epithelial cell lines with either wild-type IDH1/2 or clinically relevant IDH1/2 mutations. Differences were noted in the ability of IDH mutations to cause robust 2-HG accumulation. IDH1/2 mutants that produce high levels of 2-HG cause an epithelial-mesenchymal transition (EMT)-like phenotype, characterized by changes in EMT-related gene expression and cellular morphology. 2-HG is sufficient to recapitulate aspects of this phenotype in the absence of an IDH mutation. In the cells types examined, mutant IDH-induced EMT is dependent on upregulation of the transcription factor ZEB1 and downregulation of the mir-200 family of microRNAs. Furthermore, sustained knockdown of IDH1 in IDH1 R132H mutant cells is sufficient to reverse many characteristics of EMT, demonstrating that continued expression of mutant IDH is required to maintain this phenotype. These results suggest mutant IDH proteins can reversibly deregulate discrete signaling pathways that contribute to tumorigenesis 9 HCT116 isogenic clones with wild-type or IDH1/2 mutations. Samples were analyzed in duplicate.
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Project description:Glioblastoma (GBM) is the most frequent and most aggressive form of diffuse glioma. The prognosis is very poor, with a median overall survival of 15 months after maximum safe resection and radiochemotherapy.GBM is one of the most genetically unstable cancers. It is characterized by numerous chromosome (chr) copy number alterations (CNA), such as chr 7 gain, chr 9p loss, and chr 10 loss, along with CDKN2A homozygous deletion (chr 9p21) and EGFR amplification (chr 7p11).Chromosome instability (CIN) may be the cause or the consequence of GBM development. In high-grade diffuse gliomas (HGG), CIN may initiate tumorigenesis. To identify recurrent genomic abnormalities in IDH WT glioblastomas, SNP arrays (Illumina 850K CytoSNP) were analyzed for 123 IDH WT GBM cases.
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Project description:Gene expression of mouse hepatoblasts (HBs) expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays that were processed at the Dana-Farber Cancer Institute core facility (http://macf-web.dfci.harvard.edu/) using their standard protocol. Mutations in Isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly primary liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alphaketoglutarate (aKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple aKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks primary liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF4a, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models (GEMMs) expressing mutant IDH in the adult liver show aberrant response to hepatic injury, characterized by HNF4a silencing, impaired hepatocyte differentiation and markedly elevated levels of cell proliferation. Moreover, mutant IDH and activated Kras, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis and present a novel GEMM of IDH-driven malignancy.
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