Mutant IDH modulates suppressive myeloid populations in malignant glioma
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ABSTRACT:
PROVIDER: PRJNA1114709 | ENA |
REPOSITORIES: ENA
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Project description:RNA-sequencing for myeloid inflammation-related genes was conducted on primary tumor samples from patients with IDH-wildtype glioblastoma (GBM) and grade 4 IDH-mutant astrocytoma (G4IMA). In addition, the IDH-wildtype murine glioma cell line GL261 and a strain of IDH-mutant GL261 were also sequenced using the murine counterpart of the RNA-sequencing myeloid innate immunity panel.
2024-05-29 | GSE268118 | GEO
Project description: Not available
| S-EPMC11426330 | biostudies-literature
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-20 | GSE324694 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-20 | GSE324481 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-23 | GSE324860 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-23 | GSE327580 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-23 | GSE326221 | GEO
Project description:Isocitrate dehydrogenase (IDH)-mutant gliomas are malignant brain tumors that typically arise in early- to mid-adulthood and nearly always recur following treatment. However, the genetic and cellular state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here, we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA/RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumor types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH-wildtype glioblastoma. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were pronounced in gliomas that acquired recurrence-associated genetic events, including treatment-associated hypermutation, increased copy number changes, and cell cycle alterations. Second, increased mesenchymal-like state abundance occurred independently of acquired genetic alterations and instead coincided with heightened macrophage expression. Overall, our findings provide an integrative model that traces the cell-intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.
2026-04-20 | GSE324714 | GEO
Project description:Discovering the cell-of-origin with the initial driver mutation provides fundamental basis for understanding tumor evolution and developing new treatments. In isocitrate dehydrogenase (IDH)-mutant gliomas, the most common malignant primary brain tumors in young adult under 50, its cell-of-origin remains poorly understood. Here, we used patient brain tissues and genome edited mice to identify glial progenitor cells (GPCs) including oligodendrocyte progenitor cells (OPCs) as the cell-of-origin harboring the IDH mutation as the initial driver mutation. We conducted comprehensive deep sequencing, including droplet digital PCR and deep panel and amplicon sequencing on 128 tissues from 62 patient (29 IDH-mutant gliomas and 33 IDH-negative controls), comprising tumors, normal cortex, or normal subventricular zone (SVZ), and blood. Surprisingly, we found low-level IDH mutation in the normal cortex away from the tumor, in 38.5% (10 of 26) of IDH-mutant glioma patients, while no IDH mutation was detected in the normal SVZ. Furthermore, through the analysis of cell-type-specific mutations, the direction of clonal evolution, and the single-cell transcriptome from patient brains as well as novel mouse model of IDH-mutant glioma arising from mutation-carrying OPCs, we determined that GPCs including OPCs with the initial driver mutation are responsible for the development and evolution to IDH-mutant gliomas. In summary, our results demonstrate that GPCs containing the IDH mutation are the cells-of-origin harboring the initial driver mutation in IDH-mutant gliomas.
2026-01-13 | GSE275791 | GEO
Project description:The progression of IDH-mutant gliomas (IDH-G) from slow-growing tumors to fatal disease is associated with transcriptional and DNA methylation changes that remain poorly understood. Here, we profiled a longitudinal cohort of 36 IDH-G samples from 19 patients by joint-capture multi-omic single-nucleus (sn) DNA methylation and snRNA-seq. We show that IDH-G progression is associated with increase in malignant stem-like states, decreased differentiation and with methylation loss, which marks tumors with worse clinical outcome. Methylation loss was uniformly observed across malignant cells within individual tumors, suggesting that it may underlie rather than result from the increase in stem-like states. Analysis of cell state heritability and plasticity based on high-resolution phylogenetic trees connects DNA methylation loss to alterations in glioma cell states encoding and heritability. Our study offers insights on how DNA methylation loss reshapes cellular transitions and how it may mark clinically more aggressive tumors across IDH-G subsets.
2026-04-27 | GSE292025 | GEO