Diffuse gliomas often carry point mutations in isocitrate dehydrogenase ( IDH1), resulting in metabolic stress. Although IDH gliomas are difficult to culture in vitro, they thrive in the brain via diffuse infiltration, suggesting brain-specific tumor-stroma interactions that can compensate for IDH-1 deficits. To elucidate the metabolic adjustments in clinical IDH gliomas that contribute to their malignancy, we applied a recently developed method of targeted quantitative RNA next-generation sequencing to 66 clinical gliomas and relevant orthotopic glioma xenografts, with and without the endogenous IDH-1 mutation. Datasets were analyzed in R using Manhattan plots to calculate distance between expression profiles, Ward's method to perform unsupervised agglomerative clustering, and the Mann Whitney U test and Fisher's exact tests for supervised group analyses. The significance of transcriptome data was investigated by protein analysis, in situ enzymatic activity mapping, and in vivo magnetic resonance spectroscopy of orthotopic IDH1- and IDH-glioma xenografts. Gene set enrichment analyses of clinical IDH1 gliomas strongly suggest a role for catabolism of lactate and the neurotransmitter glutamate, whereas, in IDH gliomas, processing of glucose and glutamine are the predominant metabolic pathways. Further evidence of the differential metabolic activity in these cancers comes from in situ enzymatic mapping studies and preclinical in vivo magnetic resonance spectroscopy imaging. Our data support an evolutionary model in which IDH glioma cells exist in symbiosis with supportive neuronal cells and astrocytes as suppliers of glutamate and lactate, possibly explaining the diffuse nature of these cancers. The dependency on glutamate and lactate opens the way for novel approaches in the treatment of IDH gliomas.-Lenting, K., Khurshed, M., Peeters, T. H., van den Heuvel, C. N. A. M., van Lith, S. A. M., de Bitter, T., Hendriks, W., Span, P. N., Molenaar, R. J., Botman, D., Verrijp, K., Heerschap, A., ter Laan, M., Kusters, B., van Ewijk, A., Huynen, M. A., van Noorden, C. J. F., Leenders, W. P. J. Isocitrate dehydrogenase 1-mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress.
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http://dx.doi.org/10.1096/fj.201800907RR | DOI Listing |
Neuroradiology
January 2025
Department of Molecular Imaging and Diagnosis, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Background And Purpose: The cortical high-flow sign has been more commonly reported in oligodendroglioma, IDH-mutant and 1p/19q-codeleted (ODG IDHm-codel) compared to diffuse glioma with IDH-wildtype or astrocytoma, IDH-mutant. Besides tumor types, higher grades of glioma might also contribute to the cortical high flow. Therefore, we investigated whether the histological cortical vascular density or CNS WHO grade was associated with the cortical high-flow sign in patients with ODG IDHm-codel.
View Article and Find Full Text PDFFront Plant Sci
January 2025
National Center for Traditional Chinese Medicine (TCM) Inheritance and Innovation, Guangxi Botanical Garden of Medicinal Plants, Nanning, China.
Dihydroporphyrin iron (DH-Fe) is a novel plant growth regulator that plays significant roles in plant stress resistance. We found that is extremely sensitive to low temperature (LT) with a threshold of 25°C. To evaluate whether and how DH-Fe alleviates LT stress in , different DH-Fe concentrations (0, 10, 20, and 40 μg·L) were applied to estimate its effects on C and N metabolism and antioxidative capacity in grown under 20°C.
View Article and Find Full Text PDFArch Biochem Biophys
January 2025
Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India. Electronic address:
Heterozygous mutations in IDH1 (isocitrate dehydrogenase 1) are found in most grade II and III brain tumors. A slew of mutant IDH1 inhibitors were identified soon after the discovery of IDH1 mutations in brain tumors. But recent reports show that mutant IDH1 inhibitors reverse therapeutic vulnerabilities and activate the oncogenic transcription factor STAT3 in mutant IDH1-expressing cells.
View Article and Find Full Text PDFJ Neurooncol
January 2025
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.
Purpose: To investigate the prognostic significance of contrast enhancement (CE) in grade 2 oligodendroglioma (ODG) and explore its clinical implications.
Methods: Patients diagnosed with isocitrate dehydrogenase (IDH)-mutant, 1p/19q co-deleted ODG between 2009 and 2016 were retrospectively enrolled from a single institution. The presence of CE was identified on preoperative MRIs, and clinical, radiologic, and histopathological data that was extracted.
J Hematol Oncol
January 2025
Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
Background: Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy.
Methods: Adult patients with mIDH1 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety.
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