Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma
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PROVIDER: PRJNA1185740 | ENA |
REPOSITORIES: ENA
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Project description:The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy. We performed a high‐throughput, combination chromatin‐modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations. We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4‐mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents. Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.
2024-11-13 | GSE281811 | GEO
Project description:BackgroundThe child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy.MethodsWe performed a high-throughput, combination chromatin-modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations.ResultsWe found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4-mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents.ConclusionOur results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.
| S-EPMC11538032 | biostudies-literature
Project description:The histone methyltransferases DOT1L (H3K79me1,2,3 KMT, "activating" chromatin mark) and EZH2 (H3K27me1,2,3 KMT, "silencing" mark) have both been shown to be required for growth and survival of KMT2A rearranged AML cells. Both KMTs have been shown to modulate expression of HOXA cluster genes, albeit for EZH2 this has not been shown in the context of KMT2A rearranged AML, but in other subtypes of AML. We asked what transcriptional effects dual inhibition of DOT1L and EZH2 has in KMT2A rearranged AML.
2020-04-29 | GSE149520 | GEO
Project description:The histone methyltransferases DOT1L (H3K79me1,2,3 KMT, "activating" chromatin mark) and EZH2 (H3K27me1,2,3 KMT, "silencing" mark) have both been shown to be required for growth and survival of KMT2A rearranged AML cells. Both KMTs have been shown to modulate expression of HOXA cluster genes, albeit for EZH2 this has not been shown in the context of KMT2A rearranged AML, but in other subtypes of AML. We asked what transcriptional effects dual inhibition of DOT1L and EZH2 has in KMT2A rearranged AML.
2019-07-17 | GSE134369 | GEO
Project description:Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factors MYC and BCL6, and the epigenetic writers DOT1L and EZH2. GCB-like Diffuse Large B Cell Lymphomas (GCB-DLBCLs) arise from GC B cells and closely resemble their cell of origin. Given the dependency of GC B cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCL cell lines and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of PRC2 target genes compared to EZH2 single treatment, along with the derepression of BCL6 target genes and suppression of MYC target genes. The sum of all these alterations results in a ‘cell identity crisis,’ wherein GCB-DLBCLs lose their pro-proliferative GC identity and partially undergo plasma cell differentiation, a state associated with poor survival. In support of this model, combined epi-drugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenografts in vivo. We conclude that the malignant behavior of GCB-DLBCLs strongly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL.
2025-10-14 | PXD056212 | Pride
Project description:Previous published data suggested that DOT1L indirectly represses PRC2 target genes in murine B cell model. To address whether this relationship persists in human GCB-DLBCL, by integration of transcriptomic and epigenetic analysis, we defined the candidate direct targets of PRC2. GSEA of this genes list showed that DOT1L inhibition was able to significantly derepress candidate PRC2-target genes in Oci-Ly7 and Oci-Ly8. This effect was also observed upon combination treatment of DOT1Li and EZH2i, suggesting that DOT1L indirectly regulates the repression of PRC2 target genes. Moreover, it has been established that in the absence of Dot1l or Ezh2, GC B cells cannot maintain their identity and instead differentiate into a dysfunctional plasma cell-like state. We therefore, investigated whether the combined inhibition of DOT1L and EZH2 enhances plasma cell differentiation. We first established differentiation-state specific signatures unique for NBC, CB, MBC, PB, and BMPC using the GenomicScape database. Unsupervised clustering of the GSVA scores revealed that all the cell lines treated with the combination treatment were clustered together and gained a BMPC signature at the expense of a CB-signature. This crosstalk between DOT1L and EZH2 appeared to be conserved among different GCB-DLBCL cell lines and was independent of their responsiveness to the treatments.
2025-01-22 | GSE277665 | GEO
Project description:Purpose: To characterize transcriptional changes associated with homozygous inactivation of Dot1l or Mll1 in MN1 driven AML Methods: We sequenced mRNA from murine LSK-cells transformed using forced expression of MN1 (MSCV-MN1-IRES-GFP), and transduced with Cre-vector to inactivate either Dot1l or Mll1. Cells were sorted for Cre-expression (pTomato fluorescent marker) or expression of an inert control vector. Results: Inactivation of either Dot1l or Mll1 in this model leads to a substantial delay or complete abrogation of leukemia development. Loss of Dot1l or Mll1 are associated with gene expression changes that have substantial overlap. In addition, genes that are downregulated follwing inactivation of Dot1l or Mll1 have substantial overlap with the gene set upregulated in MN1 transduced CMPs. Conclusions: MN1 mediated leukemogenesis is associated with a gene expression program that dependes on Mll1 and Dot1l Examination of mRNA levels between Dot1l f/f and Dot1l ko, and Mll1 f/f and Mll1 ko.
2016-01-12 | E-GEOD-76748 | biostudies-arrayexpress
Project description:Purpose: To characterize transcriptional changes associated with homozygous inactivation of Dot1l or Mll1 in MN1 driven AML Methods: We sequenced mRNA from murine LSK-cells transformed using forced expression of MN1 (MSCV-MN1-IRES-GFP), and transduced with Cre-vector to inactivate either Dot1l or Mll1. Cells were sorted for Cre-expression (pTomato fluorescent marker) or expression of an inert control vector. Results: Inactivation of either Dot1l or Mll1 in this model leads to a substantial delay or complete abrogation of leukemia development. Loss of Dot1l or Mll1 are associated with gene expression changes that have substantial overlap. In addition, genes that are downregulated follwing inactivation of Dot1l or Mll1 have substantial overlap with the gene set upregulated in MN1 transduced CMPs. Conclusions: MN1 mediated leukemogenesis is associated with a gene expression program that dependes on Mll1 and Dot1l
2016-01-12 | GSE76748 | GEO
Project description:To determine whether DOT1L promotes repression of PRC2 target genes independently of EZH2, we performed H3K27me3 ChIP-seq on untreated responder Oci-Ly7 and non-responder Oci-Ly8 cell lines, and selected the top 10% of protein-coding genes with the highest H3K27me3 read counts from transcription start site +3 kilobases for subsequent analysis.
2025-01-22 | GSE277666 | GEO
Project description:Purpose: To characterize transcriptional changes associated with homozygous inactivation of Dot1l or Mll1 in MN1 driven AML Methods: We sequenced mRNA from murine LSK-cells transformed using forced expression of MN1 (MSCV-MN1-IRES-GFP), and transduced with Cre-vector to inactivate either Dot1l or Mll1. Cells were sorted for Cre-expression (pTomato fluorescent marker) or expression of an inert control vector. Results: Inactivation of either Dot1l or Mll1 in this model leads to a substantial delay or complete abrogation of leukemia development.Loss of Dot1l or Mll1 are associated with gene expression changes that have substantial overlap. In addition, genes that are downregulated follwing inactivation of Dot1l or Mll1 have substantial overlap with the gene set upregulated in MN1 transduced CMPs. Conclusions: MN1 mediated leukemogenesis is associated with a gene expression program that dependes on Mll1 and Dot1l Examination of mRNA levels between Dot1l f/f and Dot1l ko, and Mll1 f/f and Mll1 ko.
2016-01-12 | E-GEOD-76749 | biostudies-arrayexpress