K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas

Jessa, Selin; Mohammadnia, Abdulshakour; Harutyunyan, Ashot S.; Hulswit, Maud; Varadharajan, Srinidhi; Lakkis, Hussein; Kabir, Nisha; Bashardanesh, Zahedeh; Hebert, Steven C.; Faury, Damien; Vladoiu, Maria C.; Worme, Samantha; Coutelier, Marie; Krug, Brian; Andrade, Augusto Faria; Pathania, Manav; Bajic, Andrea; Weil, Alexander G.; Ellezam, Benjamin; Atkinson, Jeffrey; Dudley, Roy; Farmer, Jean‐Pierre; Perreault, Sébastien; García, Benjamin A.; Larouche, Valérie; Blanchette, Mathieu; Garzia, Livia; Bhaduri, Aparna; Ligon, Keith L.; Bandopadhayay, Pratiti; Taylor, Michael D.; Mack, Stephen C.; Jabado, Nada; Kleinman, Claudia L.

doi:10.1038/s41588-022-01205-w

Cited by 37 publications

(30 citation statements)

References 105 publications

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“…Most patients with H3 K27M-mutant spinal cord diffuse glioma are adults, and their prognosis is better than that of patients with H3 K27M-mutant brain stem tumors, mainly pediatric patients [6,9,17,19]. Recently, distinct cellular origin and prognosis characteristics have been revealed in the H3 K27M-mutant midline gliomas with different anatomic localization and ages [14,[20][21][22][23][24]. These findings gradually challenged the current situation that the clinical management of spinal cord diffuse glioma is mainly referred to guidelines of their brain counterparts [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Genomic profiling and prognostic factors of H3 K27M‐mutant spinal cord diffuse glioma

Chai

Yan

et al. 2023

Brain Pathology

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H3 K27-altered diffuse midline glioma is a highly lethal pediatric-type tumor without efficacious treatments. Recent findings have highlighted the heterogeneity among diffuse midline gliomas with different locations and ages. Compared to tumors located in the brain stem and thalamus, the molecular and clinicopathological features of H3 K27-altered spinal cord glioma are still largely elusive, thus hindering the accurate management of patients. Here we aimed to characterize the clinicopathological and molecular features of H3 K27M-mutant spinal cord glioma in 77 consecutive cases. We found that the H3 K27M-mutant spinal cord glioma, with a median age of 35 years old, had a significantly better prognosis than H3 K27M-mutant brain tumors. We noticed a molecular heterogeneity of H3 K27M-mutant spinal cord astrocytoma via targeted sequencing with 34 cases. TP53 mutation which occurred in 58.8% of cases is mutually exclusive with PPM1D (26%) and NF1 (44%) mutations. The TP53-mutant cases had a significantly higher number of copy number variants (CNV) and a marginally higher proportion of pediatric patients (age at diagnosis <18 years old, p = 0.056). Cox regression and Kaplan-Meier curve analysis showed that the higher number of CNV events (≥3), chromosome (Chr) 9p deletion, Chr 10p deletion, ATRX mutation, CDK6 amplification, and retinoblastoma protein (RB) pathway alteration are associated with worse survival. Cox regression analysis with clinicopathological features showed that glioblastoma histological type and a high Ki-67 index (>10%) are associated with a worse prognosis. Interestingly, the histological type, an independent prognostic factor in multivariate Cox regression, can also stratify molecular features of H3 K27M-mutant spinal cord glioma, including the RB pathway, KRAS/PI3K pathway, and chromosome arms CNV. In conclusion, although all H3 K27M-mutant spinal cord diffuse glioma were diagnosed as WHO Grade 4, the histological type, molecular features representing chromatin instability, and molecular alterations associated with accelerated cell proliferative activity should not be ignored in clinical management.Rui-Chao Chai and Hao Yan contributed equally to this study.

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Section: Introductionmentioning

confidence: 99%

Genomic profiling and prognostic factors of H3 K27M‐mutant spinal cord diffuse glioma

Chai

Yan

et al. 2023

Brain Pathology

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“…Recently a number of papers have described EZHIP as a PRC2 antagonist in mouse germline development and in some human cancers 57–61 . Ezhip was strongly enriched for H3K27me3 in ESCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

DNA methylation shapes the Polycomb landscape during the exit from naïve pluripotency

Albert,

Urli,

Monteagudo-Sánchez

et al. 2023

Preprint

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In mammals, 5 methyl-cytosine (5mC) and Polycomb Repressive Complex 2 (PRC2)- deposited histone 3 lysine 27 trimethylation (H3K27me3) are generally mutually exclusive at CpG-rich regions. As mouse embryonic stem cells exit the naïve pluripotent state, there is a massive gain of 5mC coincident with a restriction of broad H3K27me3 to 5mC-free, CpG-rich regions. To formally assess how 5mC shapes the H3K27me3 landscape, we profiled the epigenome of naïve and differentiated cells in the presence and absence of the DNA methylation machinery. Surprisingly, we found that 5mC accumulation is not required to restrict most H3K27me3 domains. We went on to show that this 5mC-independent H3K27me3 restriction is mediated by aberrant expression of the PRC2 antagonistEzhip. At the regions where 5mC appears to genuinely supplant H3K27me3, we identified 68 candidate genes that appeared to require 5mC deposition and/or H3K27me3 depletion for their activation in differentiated cells. Employing site-directed epigenome editing to directly modulate 5mC levels, we demonstrated that 5mC deposition is sufficient to antagonize H3K27me3 deposition and confer gene activation at individual candidates. Altogether, we systematically measured the antagonistic interplay between 5mC and H3K27me3 in a system that recapitulates early embryonic dynamics. Our results suggest that H3K27me3 restraint depends on 5mC, both directly and indirectly. This study also reveals a non-canonical role of 5mC in gene activation, which may be important not only for normal development but also for cancer progression, as oncogenic cells frequently exhibit dynamic replacement of 5mC for H3K27me3 and vice versa.

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“…Understanding how a mutation that fundamentally impairs PRC2 leads to a more nuanced outcome in a cell-type-dependent manner represents an important ongoing challenge in the study of this malignancy. 84,85 Our isogenic system also proved a powerful model in which to unravel the consequences of EZH2 gain-of-function substitutions at Y646 (Y641 in mouse) frequently found in FL. We made the surprising discovery that mutant Ezh2, long thought to require cooperation with a WT counterpart to induce changes in H3K27me3 patterns, acts autonomously to drive higher overall levels and a highly aberrant distribution of the histone mark.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

EZH2mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition

Romero

Richart

Aflaki

et al. 2023

Preprint

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Mutations in chromatin regulators or their histone substrates are widespread in cancer and often play decisive roles in tumorigenesis. These include Polycomb Repressive Complex 2 (PRC2), a histone H3 lysine 27 methyltransferase that shows distinct alterations in each of a range of tumor types. Mechanistically, this tumor- type specificity is poorly understood. Here, we model several of these alterations in a single isogenic system in order to reveal their comparative impacts on chromatin and transcription. Focusing then on gain-of-function substitutions in catalytic subunit EZH2, which occur in ~25% of follicular lymphomas, we show that Ezh2Y641F induces aberrant H3K27 methylation patterns even without wild-type Ezh2, and that these are alleviated by partial PRC2 inhibition. Ezh2Y641F also causes gains in existing H3K27 acetylation peaks and extensive gene expression changes. Remarkably, Ezh2Y641F transforms the transcriptomic response to PRC2 inhibition, leading notably to the induction of antigen presentation genes in mutant cells. Using a unique longitudinal cohort of FL patient samples we further strengthen the link between EZH2 mutation status and abnormal H3K27 methylation. This analysis also uncovered unexpected variability in the mutational landscape of successive biopsies from the same patient that points to the frequent co-existence of different clones. On a clinical level, this urges caution when stratifying patients based on single tumor sampling. Altogether, our results provide a mechanistic foundation for understanding how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.

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K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas

Cited by 37 publications

References 105 publications

Genomic profiling and prognostic factors of H3 K27M‐mutant spinal cord diffuse glioma

Genomic profiling and prognostic factors of H3 K27M‐mutant spinal cord diffuse glioma

DNA methylation shapes the Polycomb landscape during the exit from naïve pluripotency

EZH2mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition

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