bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2026–01–18
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. Autophagy Cholesterol Axis Remodeling Supports Malignant Progression and Chemoresistance in Glioma.
  2. Bevacizumab enhances overall survival in newly diagnosed glioblastoma patients with high COX-2 expression.
  3. Systemic cyst(e)inase administration induces ferroptosis and synergizes with temozolomide in glioblastoma.
  4. ON-01, an engineered recombinant oncolytic herpes simplex virus type-1, in recurrent glioma: a single-arm, phase 1/2 study.
  5. Stem Cell-Based Delivery of Immunomodulators for Overcoming Glioblastoma Immune Evasion.
  6. SMARCAL1 is a targetable synthetic lethal therapeutic vulnerability in ATRX-deficient gliomas that use Alternative Lengthening of Telomeres.
  7. A Brainstem Organoid Model Enables the Study of Pediatric Glioma at Scale.
  8. Radiotherapy plus neoadjuvant and concomitant IL-13Rα2-directed immunotoxin therapy for diffuse intrinsic pontine glioma.
  9. Characterization of a pathogenic subpopulation of human glioma associated macrophages linked to glioma progression.
  10. Human organoid tumor transplantation identifies functional glioblastoma-microenvironment communication mediated by PTPRZ1.
  11. Engineering Functionality Optimized fully human B7-H3 CAR T Cells for Enhanced Solid Tumor Therapy.
  12. KMT2A is a prerequisite of malignant transformation during IDH-mutant gliomagenesis.
  13. Boosting CAR T cell efficacy.
  1. bioRxiv. 2026 Jan 07. pii: 2026.01.06.697885. [Epub ahead of print]
    Autophagy Cholesterol Axis Remodeling Supports Malignant Progression and Chemoresistance in Glioma.
    Shahla Shojaei, Amir Barzegar Behrooz, Kianoosh Naghibzadeh, João Basso, Javad Alizadeh, Tania Dehesh, Roham Sabei, Bhavya Bhushan, Mehdi Eshraghi, Simone C da Silva Rosa, Courtney Clark, Mateusz Marek Tomczyk, Laura Cole, Grant Hatch, Vernon W Dolinsky, Vinith Yathindranath, Donald Miller, Christopher Pasco, Sanjiv Dhingra, Abhay Srivastava, Amir Ravandi, Rui Vitorino, Stevan Pecic, Negar Azarpira, Mahmoud Aghaei, Saeid Ghavami.
      Glioma progression and resistance to temozolomide (TMZ) remain major clinical challenges. Here, we investigated whether dysregulated autophagy and cholesterol metabolism are coordinately remodeled during glioma progression and TMZ resistance. Tissue microarray analysis of astrocytoma and glioblastoma specimens revealed progressive autophagosome accumulation, reflected by increased LC3β puncta, coupled with impaired autophagic flux compared with adjacent normal brain tissue. These alterations intensified with tumor grade and were associated with upregulation of farnesyl diphosphate synthase (FDPS), linking malignant progression to cholesterol pathway remodeling. TMZ-resistant (R) glioblastoma cells exhibited epithelial-to-mesenchymal transition, mitotic quiescence, and mitochondrial remodeling consistent with a therapy-tolerant phenotype. Bioenergetic profiling demonstrated reduced respiratory reserve, diminished ATP-linked respiration, and elevated proton leak, indicating constrained metabolic flexibility. In parallel, impaired autophagy flux was associated with suppression of de novo cholesterol synthesis and transcriptional downregulation of SREBP-2 and LDL-R. Comprehensive lipidomic profiling revealed marked cholesterol metabolic reprogramming in R cells, characterized by accumulation of specific cholesteryl esters, including CE 22:5, CE 22:6, CE 22:4, and CE 20:4, despite reduced cholesterol biosynthesis. Pharmacologic inhibition of the mevalonate pathway with simvastatin significantly altered cholesteryl ester profiles but failed to restore autophagy flux or sensitize R cells to TMZ-induced apoptosis, even under combined TMZ-simvastatin treatment.
    Lay Abstract: As gliomas progress from astrocytoma to glioblastoma, autophagy becomes dysregulated and cholesterol metabolism is rewired. This coordinated remodeling supports tumor survival, metabolic plasticity, and resistance to temozolomide therapy.
    Highlights: Autophagy flux blockade intensifies during progression from astrocytoma to glioblastomaDysregulated autophagy is coupled to altered cholesterol metabolism in malignant gliomasTMZ-resistant glioblastoma cells undergo epithelial-to-mesenchymal transition and mitotic quiescenceResistant cells exhibit constrained bioenergetic capacity and mitochondrial remodelingImpaired autophagy suppresses de novo cholesterol synthesis and lipid recyclingLipidomics reveals accumulation of long-chain cholesteryl esters in TMZ-resistant cellsStatin-based cholesterol inhibition fails to resensitize glioblastoma cells to temozolomide.
    DOI:  https://doi.org/10.64898/2026.01.06.697885
  2. Sci Rep. 2026 Jan 10.
    Bevacizumab enhances overall survival in newly diagnosed glioblastoma patients with high COX-2 expression.
    Irfan Kesumayadi, Atsushi Kambe, Haruto Kanda, Tomohiro Hosoya, Makoto Sakamoto, Masamichi Kurosaki.
      Bevacizumab (BEV) is known to improve progression-free survival (PFS) but not overall survival (OS) for newly diagnosed glioblastoma (ndGBM). Here, we evaluated the survival outcomes between temozolomide (TMZ)-only and TMZ + BEV treatments stratified based on the cyclooxygenase-2 (COX-2) expression, a rate-limiting enzyme involved in the cancer development. Fifty IDH-wildtype ndGBM patients treated between 2012 and 2023 were enrolled in this study. Pretreatment levels of COX-2 protein and mRNA expression were quantified, and survival analyses were performed based on the immunoreactivity score (IRS). Patients with high COX-2 expression (IRS ≥ 3, determined by its median) also exhibited higher COX-2 mRNA levels (∆Ct 6.43 ± 1.64 vs. 7.67 ± 0.81; p = 0.020). In patients with high COX-2 expression, TMZ + BEV had significantly longer median PFS and OS than those receiving TMZ-only (PFS: 22 vs. 8 months, p < 0.001; OS: 25 vs. 18 months, p = 0.009). In contrast, these benefits were not found in patients with low COX-2 expression (PFS: 12 vs. 15 months, p = 0.875; OS: 24 vs. 26 months, p = 0.775). Altogether, this study suggests that patients with high, but not low, COX-2 expression demonstrate survival benefits from the addition of BEV in ndGBM.
    Keywords:  Bevacizumab; COX-2; Newly diagnosed glioblastoma; Survival
    DOI:  https://doi.org/10.1038/s41598-026-35550-1
  3. iScience. 2026 Jan 16. 29(1): 114350
    Systemic cyst(e)inase administration induces ferroptosis and synergizes with temozolomide in glioblastoma.
    Fahim Ahmad, Blair P Rendina, Chixiang Chen, Haoyu Ren, Christine Brantner, Tijana Dukic, Delmar Miles, Jeffrey A Winkles, Graeme F Woodworth, Sarita Bhetawal, Everett Stone, Eli E Bar.
      Glioblastoma exhibits profound therapeutic resistance, driven by tumor heterogeneity and highly plastic glioma stem cells (GSCs). This study exploits GSC metabolic dependence on cysteine using systemic cyst(e)inase, a cysteine-degrading enzyme. In patient-derived GSCs and orthotopic xenograft models, cyst(e)inase potently inhibited GSC proliferation and extended animal survival by inducing ferroptosis. Mechanistically, cyst(e)inase triggered elevated reactive oxygen species (ROS), glutathione (GSH) depletion, and significant lipid peroxidation. Crucially, these effects were reversed by N-acetylcysteine (NAC), and lipid peroxidation was abrogated by the iron chelator deferoxamine (DFX), unequivocally confirming iron-dependent ferroptosis. Characteristic mitochondrial morphological changes further validated ferroptosis induction. Acyl-CoA synthetase long-chain family member-4 (ACSL4) was identified as essential for this process. Critically, cyst(e)inase synergized with temozolomide (TMZ), markedly enhancing its anti-tumor efficacy and prolonging survival, even in TMZ-resistant xenografts. These findings establish cysteine metabolism as a promising therapeutic target and position cyst(e)inase, especially with TMZ, as a potent strategy to overcome GBM resistance.
    Keywords:  microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2025.114350
  4. Neuro Oncol. 2026 Jan 12. pii: noag005. [Epub ahead of print]
    ON-01, an engineered recombinant oncolytic herpes simplex virus type-1, in recurrent glioma: a single-arm, phase 1/2 study.
    Wei Zeng, Peiwen Wang, Sheng Fang, Siqi Ge, Weifeng Jia, Shirong Peng, Mengyang Wang, Xiaoyang Qin, Wenxin Zhang, Jiajia Gao, Xiaodong Su, Guiqiang Yuan, Jiankun Wu, Yida Liu, Youwen Wang, Huacong Lu, Ran Mu, Fang Wu, Qing Chang, Guishan Jin, Fangang Meng, Junwen Zhang, Fusheng Liu.
       BACKGROUND: The prognosis of patients with recurrent WHO grade 4 glioma is poor, particularly in glioblastoma (GBM), which has a median survival of approximately 6 months and no effective treatment options. We evaluated the short-term (28-day) safety and efficacy of ON-01, an engineered recombinant oncolytic herpes simplex virus type-1, in patients with recurrent WHO grade 4 glioma.
    METHODS: In this single-arm, phase 1/2 clinical trial, eligible patients received intratumoral injections of ON-01 under stereotactic guidance. The primary endpoint was to assess the short-term safety profile of ON-01 treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the 2-year OS rate. An exploratory objective was to identify tumor-related biomarkers predictive of treatment efficacy.
    RESULTS: Of the 30 patients treated with ON-01, 13 (43.3%) were male, and the median age was 50.0 years (range, 22-75). A total of 36 grade 1, 12 grade 2, and 2 grade 3 adverse events were reported. Among all treated patients, the median OS was 12.0 months (95% CI, 10.1-13.9), median PFS was 3.0 months (95% CI, 1.7-4.3), and 2-year OS rate was 27.7% (95% CI, 12.6%-45.0%). Seven patients with recurrent multifocal gliomas demonstrated regression of non-injection site lesions following ON-01 therapy. Furthermore, patients with elevated expression of herpesvirus entry mediator exhibited significantly prolonged survival (p=0.015).
    CONCLUSIONS: Intratumoral infusion of ON-01 appeared safe and demonstrated efficacy in patients with recurrent malignant glioma, with no evidence of neurotoxicity. The therapeutic response to ON-01 may be associated with HVEM expression levels.
    Keywords:  herpes simplex virus; oncolytic virotherapy; recurrent glioma; single-arm trial
    DOI:  https://doi.org/10.1093/neuonc/noag005
  5. Immunology. 2026 Jan 13.
    Stem Cell-Based Delivery of Immunomodulators for Overcoming Glioblastoma Immune Evasion.
    Mustafa T-Ardah, H Malathi, Laxmidhar Maharana, Archana Dhyani, Shaker Al-Hasnaawei, Ashish Singh-Chauhan, Vimal Arora, Jatin Sharma, Manoj Kumar-Mishra.
      Glioblastoma (GBM) is the most aggressive primary brain tumour in adults, characterised by rapid progression, extensive heterogeneity, and poor outcomes despite surgery, radiotherapy, and temozolomide (TMZ). A subpopulation of glioblastoma stem cells (GSCs) with self-renewal and multi-lineage differentiation capabilities drives tumour initiation, progression, recurrence, and therapeutic resistance. GSCs evade conventional treatments via enhanced DNA repair, multidrug efflux, activation of survival pathways, epigenetic reprogramming, and entry into quiescent states. Moreover, these cells utilise key immune escape mechanisms, such as downregulation of major histocompatibility complex molecules and the secretion of immunosuppressive factors, to escape detection and destruction by the immune system. Evidence suggests that transformed neural stem cells are a likely source of GSCs, with key survival networks including EGFR, FGFR, HGFR, and PI3K/AKT/mTOR signalling. Their phenotypic plasticity and adaptability to the tumour microenvironment further complicate eradication. Stem cell-based strategies utilising NSCs, MSCs, haematopoietic stem/progenitor cells, or induced pluripotent stem cells can effectively deliver immunomodulators to counteract these immune evasion mechanisms, exploiting tumour tropic migration to deliver therapeutic payloads into hypoxic and infiltrative niches. Approaches such as suicide gene therapy, oncolytic virus delivery, and CXCL12-CXCR4 axis modulation aim to target both proliferative and dormant GSCs. Preclinical studies demonstrate promising efficacy, yet challenges remain, including safety concerns, variability in outcomes, and the limited translational relevance of current models. This review provides a concise overview of GSC biology, resistance mechanisms, and emerging stem cell-based interventions, highlighting opportunities and obstacles in developing effective therapies for GBM.
    Keywords:  glioblastoma; glioblastoma stem cells; stem cell therapy; targeted therapy; therapy resistance
    DOI:  https://doi.org/10.1111/imm.70102
  6. Neuro Oncol. 2026 Jan 10. pii: noaf300. [Epub ahead of print]
    SMARCAL1 is a targetable synthetic lethal therapeutic vulnerability in ATRX-deficient gliomas that use Alternative Lengthening of Telomeres.
    Alexandrea Brown, Laura M Strickland, Elise N Erman, Christopher J Pirozzi, Justin T Low, Bill H Diplas, Emiley Gibson, Mariah Shobande, Taher Khambati, Marharyta Krylova, Heng Liu, Roger E McLendon, Zachary J Reitman, Stephen T Keir, Lee Zou, David M Ashley, Matthew S Waitkus.
       BACKGROUND: Approximately 10% of cancers achieve replicative immortality through a telomerase-independent mechanism of telomere maintenance, termed Alternative Lengthening of Telomeres (ALT). ALT is particularly prevalent in certain subtypes of malignant gliomas, such as IDH-mutant astrocytoma and pediatric glioblastoma, and frequently co-occurs with ATRX inactivating mutations. Although ALT is an adaptive mechanism through which cancer cells achieve proliferative immortality, the elevated levels of replication stress observed in ALT tumors constitute a potential therapeutic vulnerability.
    METHODS: Leveraging CRISPR/Cas9 screening data from the Cancer Dependency Mapping Project, coupled with patient-derived cell lines and xenografts, we identified SMARCAL1 as a novel synthetic lethal vulnerability in ATRX-deficient glioma models that engage ALT. Using complementary molecular assays for DNA damage, telomere maintenance, and telomeric replication stress, we define the mechanisms underlying cytotoxicity induced by SMARCAL1 depletion in ALT-positive glioma cells.
    RESULTS: Our data demonstrate the annealing helicase SMARCAL1 is a highly specific synthetical lethal vulnerability in cancers that use ALT. SMARCAL1 localizes to ALT-associated PML bodies in ALT-positive glioma cell lines, including IDH-mutant astrocytomas. SMARCAL1 depletion, via doxycycline-induced RNAi, led to a hyperactivation of the ALT phenotype, high levels of DNA double-strand breaks in G2 phase, and cell death via mitotic catastrophe. In mice bearing intracranial xenografts derived from high-grade IDH-mutant astrocytoma, inducible SMARCAL1 depletion prolonged animal survival.
    CONCLUSIONS: Our findings demonstrate that the molecular processes orchestrating ALT-mediated telomere maintenance constitute a targetable synthetic lethal vulnerability that can be exploited by SMARCAL1 inhibition, thus supporting the future development of small molecule inhibitors of SMARCAL1 as anti-cancer therapeutics.
    DOI:  https://doi.org/10.1093/neuonc/noaf300
  7. Cancer Discov. 2026 Jan 14. OF1
    A Brainstem Organoid Model Enables the Study of Pediatric Glioma at Scale.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2025-006
  8. Commun Biol. 2026 Jan 15.
    Radiotherapy plus neoadjuvant and concomitant IL-13Rα2-directed immunotoxin therapy for diffuse intrinsic pontine glioma.
    Julian S Rechberger, Wouter J F Vanbilloen, Leo F Nonnenbroich, Jizhi Ge, Randy S Schrecengost, Rachael A Vaubel, Liang Zhang, David J Daniels.
      Radiotherapy (RT) is the standard-of-care for diffuse intrinsic pontine glioma (DIPG); however, it functions as a palliative treatment. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is upregulated in most DIPG tumors, posing a promising therapeutic target. Immunotherapies harnessing IL-13Rα2 to selectively deliver cytotoxic payloads such as pseudomonas exotoxin A (PE) are safe in DIPG patients and efficacious in preclinical disease models. Here, we used DIPG cell lines and mouse models to compare RT alone with RT plus the IL-13Rα2-targeted PE immunotoxin GB13 (IL13.E13K-PE4E). DNA strand breaks were evaluated by γH2AX and apoptosis, as well as other on-target effects, by Western blot and immunofluorescence. Cell viability and colony formation assays delineated cell viability and proliferation. In vivo efficacy was based on survival of mice with orthotopic tumors. Animals received fractionated focal irradiation and neoadjuvant and concomitant GB13 by convection-enhanced delivery. GB13 improved the efficacy of RT in vitro through inhibition of DNA damage repair and convergent modulation of apoptotic signaling. Combined RT and intratumoral administration of GB13 decreased tumor burden and prolonged survival in orthotopic xenograft and genetically engineered mouse models. These findings indicate that RT plus GB13 is well tolerated and effective, informing future investigation of a novel therapeutic approach for DIPG.
    DOI:  https://doi.org/10.1038/s42003-025-09155-9
  9. Cancer Cell. 2026 Jan 12. pii: S1535-6108(25)00544-6. [Epub ahead of print]44(1): 129-145.e12
    Characterization of a pathogenic subpopulation of human glioma associated macrophages linked to glioma progression.
    Kenny Kwok Hei Yu, Zaki Abou-Mrad, Kristof Törkenczy, Isabell Schulze, Jennifer Gantchev, Gerard Baquer, Kelsey Hopland, Evan D Bander, Umberto Tosi, Cameron Brennan, Nelson S Moss, Pierre-Jacques Hamard, Richard Koche, Caleb Lareau, Nathalie Y R Agar, Taha Merghoub, Viviane Tabar.
      Primary de novo high grade gliomas, such as glioblastoma and lower grade gliomas both converge on a common aggressive phenotype, and the basis for this progression is unknown. Glioma associated macrophages (GAM) have been strongly implicated in supporting tumor growth, however, robust isolation of functional subpopulations has been elusive. We hypothesize that functional populations of GAMs can be resolved through gene regulatory network (GRN) inference and show that a subpopulation of human GAMs, defined by a GRN centered around the activator protein-1 transcription factor FOSL2 is preferentially enriched in high grade gliomas. We nominate ANXA1 and HMOX1 as surrogate cell surface markers for a subpopulation we term malignancy associated GAMs (mGAMs) which possess distinct pro-tumorigenic properties, share partial ontogeny with peripheral blood monocytes, and are enriched in newly transformed regions of glioma. mGAMs potentially play a pivotal role in glioma progression and represent a plausible therapeutic target.
    Keywords:  ANXA1; FOSL2; HMOX1; gene regulatory network; glioma; glioma associated macrophage; low-grade glioma; transformation
    DOI:  https://doi.org/10.1016/j.ccell.2025.12.010
  10. Cell Rep. 2026 Jan 14. pii: S2211-1247(25)01620-1. [Epub ahead of print]45(1): 116848
    Human organoid tumor transplantation identifies functional glioblastoma-microenvironment communication mediated by PTPRZ1.
    Weihong Ge, Ryan L Kan, Can Yilgor, Elisa Fazzari, Patricia R Nano, Daria J Azizad, Heer Shinglot, Matthew Li, Joyce Y Ito, Christopher Tse, Hong A Tum, Jessica Scholes, Shivani Baisiwala, Kunal S Patel, David A Nathanson, Aparna Bhaduri.
      Glioblastoma is the most aggressive and deadly form of brain cancer. Here, we leverage our human organoid tumor transplantation (HOTT) co-culture system to explore how extrinsic cues modulate glioblastoma cell types and behavior. HOTT recapitulates core features of major patient tumor cell types and key aspects of neural cell-enriched tumor microenvironment (nTME) gene programs. Our exploration of patient TME interactions preserved in HOTT highlights four receptor-ligand interactions of interest. We knock down all four of these genes in the HOTT microenvironment. We observe that knocking down nTME PTPRZ1, a receptor tyrosine phosphatase implicated in cancer cell migration, results in an increased fraction of mesenchymal cells, enrichment of epithelial-to-mesenchymal gene programs, and an elevated tumor microtube length in co-cultured primary patient tumors. This phenotype is not mediated by PTPRZ1's catalytic activity, suggesting a mechanism of tumor cell fate driven by nTME PTPRZ1, highlighting the strengths of the HOTT system.
    Keywords:  CP: Cancer; CP: Stem cell research; PTPRZ1; glioblastoma; human organoid tumor transplantation; organoid models of brain cancer; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2025.116848
  11. bioRxiv. 2026 Jan 09. pii: 2026.01.09.696281. [Epub ahead of print]
    Engineering Functionality Optimized fully human B7-H3 CAR T Cells for Enhanced Solid Tumor Therapy.
    Pradip Bajgain, Yang Feng, Mariela Puebla, Meijie Tian, Kuo-Sheng Hsu, Jaewon Lee, GuoJun Yu, Liping Yang, Steven Seaman, Mary Beth Hilton, Karen Morris, Niza Borchin, Jennifer D Tran, Riley D Metcalfe, James C Cronk, Javed Khan, Anandani Nellan, Rosandra N Kaplan, Brad St Croix.
      B7-H3 is a cell surface protein overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR) T cell therapy. The most clinically advanced B7-H3 CARs are derived from murine monoclonal antibodies (mAbs) 376.96 and MGA271, which are now in phase 1/11 trials. However, non-human mAb sequences can provoke immune responses, leading to CAR T-cell rejection and therapeutic failure. Although scFv humanization reduces this risk, residual foreign residues within the variable domains remain. To overcome this limitation, we used in vitro phage display to generate fully human B7-H3-specific scFvs for CAR design. In pancreatic cancer, neuroblastoma, and glioblastoma xenograft models, CAR T cells incorporating the lead human binder Y111 were well tolerated and demonstrated superior antitumor activity compared with 376.96- and MGA271-based CARs. Y111 CAR treatment induced complete responses, tumor rejection, and significant survival benefits, identifying Y111 as a promising fully human B7-H3 CAR for solid tumors.
    DOI:  https://doi.org/10.64898/2026.01.09.696281
  12. Neuro Oncol. 2026 Jan 14. pii: noag006. [Epub ahead of print]
    KMT2A is a prerequisite of malignant transformation during IDH-mutant gliomagenesis.
    Marilin S Koch, Minh Deo, Claudia Schmidt, Adrianna Podolak, Julian Taranda, Michael S Hoetker, Şevin Turcan.
       BACKGROUND: IDH1R132H is the defining mutation of low-grade gliomas (LGGs), inflicting broad epigenetic rewiring that leads to malignant transformation. Recent studies demonstrated that cell fate change from astrocyte to LGG is accompanied by redistribution of H3K4 methylation. By modulating H3K4-methyltransferase KMT2A in a conditionally IDH1R132H-expressing human astrocyte model system, we sought to define requirements of IDH1R132H dependent gliomagenesis and identify novel therapeutic targets.
    METHODS: Using KMT2A inhibitor MM-102, we targeted H3K4me3 in IDH1R132H -expressing astrocytes, profiling L1CAM expression, proliferation, clonogenicity, invasion and migration, transcriptional and translational changes. Findings were validated in patient-derived IDH1R132H glioma lines with shRNA-mediated knockdown. Epigenetic transformation was characterized with CUT&Tag and MethylationEPIC. Downstream targets were assessed utilizing siRNAs.
    RESULTS: KMT2A inhibition significantly decreased L1CAM expression and led to broad transcriptional downregulation, including LGG marker genes. Analyses of transcriptomics and proteomics pointed to altered lipid metabolism and migratory capacity. Phenotypic characterization showed impaired invasion, migration and proliferation. We observed significantly reduced deposition of H3K4me3 at promoters of DEGs and enhanced global DNA methylation. We identified SCD as putative KMT2A-dependent effector whose knockdown reduced clonogenicity. In patient-derived models, KMT2A suppression impaired viability and spheroid growth in vitro; however, in an orthotopic TS603 model, knockdown shortened survival, indicating stage- and context-dependent effects.
    CONCLUSIONS: Disrupting KMT2A-mediated H3K4me3 reshapes the epigenome and attenuates LGG-relevant programs and phenotypes in vitro, supporting a strong role in tumor initiation. In vivo, the TS603 survival result highlights context-dependent maintenance and motivates cautious, microenvironment-aware therapeutic exploration of the KMT2A axis and downstream targets such as SCD.
    Keywords:  H3K4me3; KMT2A; epigenetics; gliomagenesis; low-grade glioma
    DOI:  https://doi.org/10.1093/neuonc/noag006
  13. Nat Rev Drug Discov. 2026 Jan 12.
    Boosting CAR T cell efficacy.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-026-00005-9
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