Project description:Mutations in the enzymes IDH1 and IDH2 have been identified in a wide variety of tumors like glioma, chondrosarcoma, thyroid cancer, lymphoma, melanoma, and in acute myeloid leukemia. Mutated IDH1/2 produces the metabolite 2-hydroxyglutarate (2HG), which interferes with epigenetic regulation of gene expression, and thus may promote tumorigenesis. HoxA9 immortalised bone marrow cells from C57BJ/6 mice were tranduced with either empty vector or pSF91-IDH1wt-IRES-EGFP, or pSF91-IDH1mut-IRES-GFP and transplanted in irradiated recipient mice. Alternatively, HoxA9 immortalised cells transduced with empty vector transplanted mice were treated with R-2HG at dose of 1mg/day for four weeks. Four weeks after transplantation/treatment GFP+ cells were sorted from mouse bone marrow, from which total RNA ws extracted and subjected to microarray analysis.
Project description:Mutations in the enzymes IDH1 and IDH2 have been identified in a wide variety of tumors like glioma, chondrosarcoma, thyroid cancer, lymphoma, melanoma, and in acute myeloid leukemia. Mutated IDH1/2 produces the metabolite 2-hydroxyglutarate (2HG), which interferes with epigenetic regulation of gene expression, and thus may promote tumorigenesis. HoxA9 immortalised bone marrow cells from C57BJ/6 mice were tranduced with either empty vector or pSF91-IDH1wt-IRES-EGFP, or pSF91-IDH1mut-IRES-GFP and transplanted in irradiated recipient mice. Alternatively, HoxA9 immortalised cells transduced with empty vector transplanted mice were treated with R-2HG at dose of 1mg/day for four weeks. Four weeks after transplantation/treatment GFP+ cells were sorted from mouse bone marrow, from which total DNA was extracted and subjected to Reduced Representation Bisulfite Sequencing (RRBS) to determine the genome-wide methylation signature.
Project description:Mutations in the enzymes IDH1 and IDH2 have been identified in a wide variety of tumors like glioma, chondrosarcoma, thyroid cancer, lymphoma, melanoma, and in acute myeloid leukemia. Mutated IDH1/2 produces the metabolite 2-hydroxyglutarate (2HG), which interferes with epigenetic regulation of gene expression, and thus may promote tumorigenesis. HoxA9 immortalized bone marrow cells from C57BJ/6 mice were transduced with either empty vector or pSF91-IDH1wt-IRES-EGFP, or pSF91-IDH1mut-IRES-GFP and transplanted in irradiated recipient mice. Four weeks after transplantation, GFP+ cells were sorted from mouse bone marrow, from which total RNA was extracted and subjected to microarray analysis.
Project description:Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring a mutation in isocitrate dehydrogenase 1 mutation (IDH1mut) acquire a different tumor biology and clinical manifestation than those that are IDH1WT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we discovered increased monounsaturated fatty acids (MUFA) and their phospholipids in ER, generated by IDH1 mutation, that were responsible for Golgi and ER dilation. We demonstrated a direct link between the IDH1 mutation and these organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate-limiting enzyme in MUFA biosynthesis. Inhibition of IDH1 mutation or SCD silencing restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilted the balance towards elevated levels of MUFA, produced IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.
Project description:Gene expression changes induced by BAY1436032 (IDH1mut inhibitor) in sorted human (CD45+) cells from bone marrow of IDH1mut patient derived xenotransplantation mice model
Project description:The purpose of the study is to compare the protein changes between cirrhosis control and therapy groups for bone marrow-sorted LSK cells.
Project description:<p>Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring an isocitrate dehydrogenase 1 mutation (IDHmut), acquire a different tumor biology and clinical manifestation than those that are IDHWT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we discovered monounsaturated (MUFA) to polyunsaturated (PUFA) lipid imbalances in organelles, generated by IDH mutation in cells and patient tissue, that were responsible for Golgi and ER dilation. We demonstrated a direct link between the IDH mutation and these organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate limiting enzyme in MUFA biosynthesis. Inhibition of IDH mutation or SCD silencing restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilted the balance towards elevated levels of MUFA, produced IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the biodistribution of lipids in the organelles of glioma, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.</p><p><br></p><p>Linked studies;</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1967' rel='noopener noreferrer' target='_blank'>MTBLS1967</a> FA_HILICZ</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1974' rel='noopener noreferrer' target='_blank'>MTBLS1974</a> LCMS(CSHPos)</p>