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Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG)

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE250467 | GEO | 2025/02/03

REPOSITORIES: GEO

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Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [HiC]

Project description:Diffuse intrinsic pontine glioma (DIPG), an exceptionally lethal pediatric cancer with limited treatment options, is characterized by relentless proliferation and differentiation arrest, primarily influenced by H3K27M oncohistones. This study unveils that ID1 activation occurs independently of BMP signaling in H3.3K27M/ACVR1WT DIPG subtype. ID1 inhibition promotes cell differentiation and apoptosis in DIPG. Additionally, we discover the intricate regulation of ID1 tied to the lineage-specific transcription factor CREB5—an oncogenic contributor hindering differentiation in the H3.3K27M subtype of DIPG. The SWI/SNF complex is identified as a co-regulator of CREB5, further promoting tumorigenesis. Intriguingly, H3.3K27M oncohistones act as a trigger for CREB5 overexpression, facilitating the formation of super-enhancer promoter loops. Moreover, our research highlights the potent anti-tumor effect of ABBV-075 in treating DIPG. In essence, this study elucidates the oncohistone-driven H3.3K27M/CREB5/ID1 axis, providing insights into the malignant cellular state within a DIPG subtype and offering potential therapeutic avenues for this devastating pediatric cancer.

2025-02-03 | GSE277795 | GEO

Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [RNA-seq]

2025-02-03 | GSE250466 | GEO

Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [CUT&Tag]

2025-02-03 | GSE250464 | GEO

Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [ATAC-seq]

2025-02-03 | GSE250461 | GEO

Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG)

Project description:Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG)

| PRJNA1054113 | ENA

Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [HiC]

Project description:Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [HiC]

| PRJNA1164208 | ENA

Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [ATAC-seq]

Project description:Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [ATAC-seq]

| PRJNA1054108 | ENA

Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [CUT&Tag]

Project description:Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [CUT&Tag]

| PRJNA1054111 | ENA

Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [RNA-seq]

Project description:Oncohistone H3.3K27M-driven CREB5/ID1 Axis Mediates the Malignant Cell States of Diffuse Intrinsic Pontine Glioma (DIPG) [RNA-seq]

| PRJNA1054114 | ENA

DIPG-32. AKT SIGNALING DRIVES RESISTANCE TO ONC201 IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Project description:Abstract Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive, childhood brainstem cancer with a median overall survival of 10 months post diagnosis. Remarkably, 80–90% of patients harbor recurring point mutation in histone H3, which induces a lysine for methionine substitution at amino acid 27 (H3K27M) in either H3.1 (HIST1H3B ~25%) or H3.3 (H3F3A ~65%) variants. Using the blood-brain barrier (BBB) permeable DRD2 antagonist, ONC201 (in clinical trials for DIPG and H3K27M-mutant gliomas – NCT03416530), we hypothesized that DRD2 antagonism would induce TRAIL expression via indirect inhibition of AKT and ERK signaling, to drive apoptosis in both H3.1K27M and H3.3K27M patient-derived DIPG cell lines alike. For the first time, we reveal that ONC201 shows efficacy in 100% of WT-H3 and H3.1K27M mutant DIPG cell lines (n=5), compared to 50% of H3.3K27M mutant DIPGs (n=6). Investigations to identify the mechanisms of resistance to ONC201, revealed that cell lines with decreased sensitivity upregulated the PI3K/AKT/MTOR signaling axis to drive phosphorylation of AKT and increase metabolic activity. Combined administration of ONC201 and the BBB-permeable PI3K/AKT inhibitor, paxalisib (previously GDC-0084, in clinical trials for newly diagnosed DIPG – NCT03696355), showed synergistic cytotoxicity, reduced PI3K/AKT signaling and metabolic reprogramming to drive apoptosis in all DIPG cell lines tested. This combination was used to treat a 3-year-old DIPG patient, commencing 14 weeks post disease progression, completing 40 weeks of therapy prior to her passing, December 2019. These studies highlight the potential of combined administration of two safe, BBB penetrant, oral targeted therapies and supports testing under clinical trial conditions.

| S-EPMC7715600 | biostudies-literature

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