MAT2A expression and methionine dependency in Diffuse Midline Gliomas creates a distinct metabolic and epi-genetic sensitivity
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE160088 | GEO | 2022/01/28
REPOSITORIES: GEO
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Project description:Gliomas bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors. H3K27M mutant tumors display unique epigenomes with global loss of the chromatin repressive H3K27 trimethylation mark. Here, we generated a syngeneic H3K27M mouse model to study the dependence upon amino acid (AA) metabolism by performing an AA drop out screen. H3K27M mutant cells, but not histone wildtype cells, were highly dependent on the amino acid, methionine. Interrogating the methionine cycle dependency through an siRNA screen identified the enzyme Methionine Adenosyltransferase 2A (MAT2A), which catalyzes production of S-adenosylmethionine (SAM), a methyl donor. Sensitivity to MAT2A loss in H3K27M mutant cells was not mediated through the canonical mechanism of MTAP deletion; instead, H3K27M mutant cells have lower MAT2A protein levels, which is mediated by Adenosylmethionine Decarboxylase 1 (AMD1) production of decarboxylated SAM (dcSAM). MAT2A loss induces global depletion of H3K36me3, a potent chromatin mark of transcriptional elongation, as evaluated by quantitative chromatin immunoprecipitation with reference exogenous genome sequencing (ChIP-Rx-Seq) in multiple DIPG lines. Tandem H3K36me3 ChIP-Rx-seq and RNA-seq identified several oncogenic and developmental transcriptional programs associated with MAT2A loss. Moreover, inducible knockdown of MAT2A or methionine-restricted diets (MR) extended survival in both syngeneic and patient-derived xenograft models (PDXs) in vivo. Collectively, our results provide novel connections between AA metabolism and the epigenome in H3K27M gliomas, suggesting that MAT2A, a central regulator of methionine metabolism, presents exploitable therapeutic vulnerabilities in H3K27M gliomas.
2022-01-28 | GSE160006 | GEO
Project description:Characterisation of a new subgroup of DMG lacking H3-K27M mutation that is defined by H3K27me3 loss and EZHIP overexpression that can be detected by IHC. These tumors are distinct from EZHIP-positive posterior fossa ependymomas and are associated with a dismal prognosis. We propose that these EZHIP/H3-WT tumors need to be considered similar to canonical DIPG/DMG, thus extending the spectrum of DMG with PRC2 inhibition beyond H3-K27M mutation
2020-03-20 | E-MTAB-8888 | biostudies-arrayexpress
Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.
2023-05-25 | PXD036245 | Pride
Project description:Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal central nervous system (CNS) tumors that occur most commonly in children and young adults1. Average life expectancy is ten months from diagnosis, and 5-year survival is less than 1%2. Palliative radiotherapy is the only established treatment3, and neither cytotoxic nor targeted pharmacological approaches have demonstrated anti-tumor responses or improved prognosis to date3,4. We previously discovered that the disialoganglioside GD2 is highly and uniformly expressed on H3K27M+ DMG cells and demonstrated that intravenously (IV) administered GD2.4-1BB.z chimeric antigen receptor (CAR) T-cells eradicated established DMGs in patient-derived orthotopic murine models5, thereby providing the rationale for a first-in-human/first-in-child Phase 1 clinical trial (NCT04196413). Because CAR T-cell-induced inflammation and edema of the brainstem can result in obstructive hydrocephalus, increased intracranial pressure, and dangerous tissue shifts, a number of neurocritical care precautions were incorporated in the clinical trial design and management plan. Here we present the clinical experience from the first four patients with H3K27M+ DMG treated with GD2-CAR T-cells at dose level 1 (DL1; 1e6 GD2-CAR T-cells/kg administered IV). Patients who exhibited clinical benefit were eligible for subsequent administrations of GD2-CAR T-cells. Given preclinical evidence for increased CAR T-cell potency6, and the potential for diminished immunogenicity with locoregional administration, second doses were administered intracerebroventricularly (ICV) through an Ommaya catheter to three patients. As predicted from preclinical models, toxicity was largely related to the neuroanatomical location of the tumors and was reversible with intensive supportive care. Although GD2 is expressed at low levels in normal neural tissue, no evidence of on-target, off-tumor toxicity was observed. Three of four patients exhibited clinical and radiographic improvement, underscoring the promise of this approach for H3K27M+ DMG therapy. Correlative studies of serum and CSF revealed marked proinflammatory cytokine production following GD2 CAR T cell administration and single cell transcriptomic analysis of 65,598 single cells from CAR T cell products and patient CSF has begun to reveal differences that correlate with the heterogeneity between subjects and routes of administration.
2022-02-07 | GSE186802 | GEO
Project description:Diffuse midline gliomas (DMG) are a group of molecularly related malignancies occurring in midline structures of the childhood central nervous system, including thalamus, pons, and spinal cord. These cancers are characterized by high prevalence of the histone-3K27M mutation and are universally lethal, with median survival of only 9-11 months for pontine DMG (a.k.a. DIPG). In search of novel therapeutic options, we examined multiple cell models in sequential, quantitative high-throughput screens of approved and investigational drugs. This effort generated a total of 17,456 single-agent dose responses that inspired a subsequent series of HTS-enabled drug combination assessments encompassing a total of 8883 drug-drug examinations. Top combinations were validated across a panel of patient-derived cell lines representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-HDAC inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to the cellular unfolded protein response and key metabolic processes following treatment with panobinostat and marizomib. Rescue of drug induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking NAD+ production via NAMPT inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study represents the most comprehensive single-agent and combinatorial drug screen for DIPG reported to date and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores under-recognized metabolic vulnerabilities in DIPG. The combined screening outcomes represent a public resource for the DMG community.
2019-11-29 | GSE123278 | GEO
Project description:MAT2A expression and methionine dependency in Diffuse Midline Gliomas creates a distinct metabolic and epi-genetic sensitivity
| PRJNA671811 | ENA
Project description:H3K27-altered Diffuse Midline Glioma (DMG) is a universally fatal paediatric brainstem tumour. The prevalent driver mutation H3K27M creates a unique epigenetic landscape that may also establish therapeutic vulnerabilities to epigenetic inhibitors. From a wider screen of an epigenetic inhibitor library, we identified PRMT5 inhibitors as amongst the top hits reducing DMG cell viability. Here, we treated HSJD-DIPG-007 +/- the PRMT5 inhibitor LLY-283. RNA-sequencing was performed at 0, 1, 2, 3, 5, 7 and 10 days to assess the changes in gene expression following PRMT5 inhibition in DMG cells. This shows that PRMT5 inhibition changes expression in genes associated with multiple disease relevant phenotypes, including sterol metabolism, differentiation, and the extracellular matrix. By characterising the changes in the transcriptome following PRMT5 inhibition this provides crucial insights into the potential of PRMT5 inhibitors as a treatment for H3K27-altered DMG.
2024-01-05 | GSE230065 | GEO
Project description:Diffuse midline gliomas (DMGs) are universally fatal pediatric brain tumors associated with mutations in genes encoding either histone H3.1 or histone 3.3, often substitution of methionine for lysine 27 (H3K27M). H3K27 is a critical determinant of chromatin state via methylation by Enhancer-of-Zeste-Homolog-2 (EZH2). Previous reports have suggested that the pathologically low levels of H3K27me3 found in histone-mutant DMGs result primarily from H3K27M inhibiting EZH2 directly, but recent reports have called this model into question. To better understand the chromatin landscape of DMGs, we applied CUT&RUN to patient-derived DMG cell lines. Remarkably, we find that the PRC2 activity is similar in DMGs and embryonic stem cells, suggesting a primitive cell-of-origin, despite transcriptionally active regions maintaining markers of both stem cells and differentiated cells. We also show that exogenous expression of H3.3M at physiological levels has little effect on H3K27me3 levels, that H3K27M can colocalize with H3K27me3 in vivo and that the H3.3K27M oncohistone does not show evidence of sequestering PRC2 components. Our results suggest that chromatin landscapes in DMGs are a consequence of a stem-like chromatin state that is retained despite activation of differentiation programs. Our findings have implications for understanding DMG gliomagenesis and therapeutic approaches centered on epigenome-modifying agents.
2020-09-08 | GSE118099 | GEO
Project description:MAT2A and methionine dependency are indispensible for H3K27M mutant gliomas.
| PRJNA671595 | ENA
Project description:Diffuse intrinsic pontine gliomas (DIPG) are characterized by a heterozygous lysine-to-methionine mutation of histone H3 (H3K27M) that potently reduces Polycomb Repressive Complex 2 (PRC2) methylation of wild-type histone H3K27 (H3K27wt). The role of H3K27M and reduced H3K27wt methylation in DIPG pathogenesis has yet to be determined. Here, we have performed epigenomic profiling of patient-derived H3K27M mutant DIPG cells and demonstrate that H3K27M resides in nucleosomes with H3K27wt acetylation (H3K27ac), and H3K27M-H3K27ac containing nucleosomes co-localize with bromodomain proteins at actively transcribed genes and that PRC2 is excluded from H3K27M occupied regions. With respect to therapeutic implications of these observations, we demonstrate that pharmacologic bromodomain protein inhibition suppresses tumor growth in vivo. In total, our results indicate that H3K27M promotes H3K27ac at the expense of H3K27 methylation, and points to bromodomain protein inhibition as a clinical strategy for treating DIPG.
2017-02-27 | GSE78801 | GEO