9a38fa75-7fb7-44a1-b0cd-eb0406390202 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001007768 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:We profiled transcriptome and epigenome of BMP signaling effects on H3.3K27M DIPG
| EGAS00001005374 | EGA
Project description:Diffuse intrinsic pontine glioma (DIPG), a lethal pediatric cancer driven by H3K27M oncohistones, exhibits aberrant epigenetic regulation and stem-like cell states. Here, we uncover an axis involving H3.3K27M oncohistones, CREB5/ID1, which sustains the stem-like state of DIPG cells, promoting malignancy. We demonstrate that CREB5 mediates elevated ID1 levels in the H3.3K27M/ACVR1WT subtype, promoting tumor growth; while BMP signaling regulates this process in the H3.1K27M/ACVR1MUT subtype. Furthermore, we reveal that H3.3K27M directly enhances CREB5 expression by reshaping the H3K27me3 landscape at the CREB5 locus, particularly at super-enhancer regions. Additionally, we elucidate the collaboration between CREB5 and BRG1, the SWI/SNF chromatin remodeling complex catalytic subunit, in driving oncogenic transcriptional changes in H3.3K27M DIPG. Intriguingly, disrupting CREB5 super-enhancers with ABBV-075 significantly reduces its expression and inhibits H3.3K27M DIPG tumor growth. Combined treatment with ABBV-075 and a BRG1 inhibitor presents a promising therapeutic strategy for clinical translation in H3.3K27M DIPG treatment.
2025-01-28 | PXD053094 | Pride
Project description:Diffuse intrinsic pontine glioma (DIPG), a lethal pediatric cancer driven by H3K27M oncohistones, exhibits aberrant epigenetic regulation and stem-like cell states. Here, we uncover an axis involving H3.3K27M oncohistones, CREB5/ID1, which sustains the stem-like state of DIPG cells, promoting malignancy. We demonstrate that CREB5 mediates elevated ID1 levels in the H3.3K27M/ACVR1WT subtype, promoting tumor growth; while BMP signaling regulates this process in the H3.1K27M/ACVR1MUT subtype. Furthermore, we reveal that H3.3K27M directly enhances CREB5 expression by reshaping the H3K27me3 landscape at the CREB5 locus, particularly at super-enhancer regions. Additionally, we elucidate the collaboration between CREB5 and BRG1, the SWI/SNF chromatin remodeling complex catalytic subunit, in driving oncogenic transcriptional changes in H3.3K27M DIPG. Intriguingly, disrupting CREB5 super-enhancers with ABBV-075 significantly reduces its expression and inhibits H3.3K27M DIPG tumor growth. Combined treatment with ABBV-075 and a BRG1 inhibitor presents a promising therapeutic strategy for clinical translation in H3.3K27M DIPG treatment.
2025-01-28 | PXD060271 | Pride
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
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 | GSE250466 | GEO
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 | GSE250464 | GEO
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 | GSE250461 | GEO
Project description:Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the BMP/K27M crosstalk.
2024-06-03 | GSE268577 | GEO
Project description:Diffuse intrinsic pontine gliomas (DIPG) are devastating pediatric brain tumors for which there is no effective therapy. A lack of pre-clinical genetic models has affected efforts to develop therapies targeted to DIPG. Over 60% of DIPG patients carry a mutation in the histone H3F3A gene (H3.3K27M) that is often accompanied by a mutation in the TP53 gene. Here we created a genetic model in which H3.3K27M is expressed under the mouse Fabp7 promoter. These mice have disrupted embryonic development and increased susceptibility to development of lymphomas. Crosses to Trp53 knockout mice further accelerated lymphomagenesis and led to brain tumour development. Some but not all tumours acquired additional oncogenic alterations. The brain tumours faithfully recapitulate the expression profiles of DIPG patients, and brain tumours and lymphomas share significant similarities in pathway alterations, pointing to a core H3.3K27M transcriptome. Overall, this mouse model provides key insights into how H3.3K27M mutations regulate DIPG at the cellular and tumour level.
2020-10-27 | GSE120883 | GEO
Project description:Diffuse intrinsic pontine gliomas (DIPG) are devastating pediatric brain tumors for which there is no effective therapy. A lack of pre-clinical genetic models has affected efforts to develop therapies targeted to DIPG. Over 60% of DIPG patients carry a mutation in the histone H3F3A gene (H3.3K27M) that is often accompanied by a mutation in the TP53 gene. Here we created a genetic model in which H3.3K27M is expressed under the mouse Fabp7 promoter. These mice have disrupted embryonic development and increased susceptibility to development of lymphomas. Crosses to Trp53 knockout mice further accelerated lymphomagenesis and led to brain tumour development. Some but not all tumours acquired additional oncogenic alterations. The brain tumours faithfully recapitulate the expression profiles of DIPG patients, and brain tumours and lymphomas share significant similarities in pathway alterations, pointing to a core H3.3K27M transcriptome. Overall, this mouse model provides key insights into how H3.3K27M mutations regulate DIPG at the cellular and tumour level.
2020-10-27 | GSE120882 | GEO