Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas

ABSTRACT: KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas

PROVIDER: PRJNA643585 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR12030900_1.fastq.gz	Fastqsanger.gz
	SRR12030900_2.fastq.gz	Fastqsanger.gz
	SRR12030901_1.fastq.gz	Fastqsanger.gz
	SRR12030901_2.fastq.gz	Fastqsanger.gz
	SRR12030902_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 211

Similar Datasets

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [1]

Project description:Loss of function mutations within KMT2D are a striking feature of the germinal centre lymphomas, with lesions present in 80% of Follicular Lymphoma (FL) and 30% of Diffuse Large B-cell Lymphoma (DLBCL), resulting in decreased H3K4 methylation and altered gene expression. The KDM5 family normally maintains homeostasis through demethylating H3K4me3/2, thus negatively regulating gene expression. We hypothesised that inhibition of KDM5 may re-establish H3K4 methylation and restore the expression of genes repressed upon loss of KMT2D. Using a selective inhibitor of the KDM5 family we were able to increase H3K4me3 levels in DLBCL cell lines, predominantly at gene promoters, ultimately leading to decreased proliferation and cell death in KMT2D mutant cell lines. This appeared to be driven by an increase in the expression of negative regulators of B cell survival pathways, many of which have previously been described as targets of KMT2D and CREBBP, resulting in diminished BCR signalling. We also observed decreased BCL2 expression in all examined t(14;18) positive cell lines, alongside changes in other BCL2 family members in sensitive cell lines. KDM5 sensitivity was confirmed to be dependent on the presence of KMT2D mutations by generating de novo KMT2D mutant cell lines and correcting naturally mutant cell lines, which displayed greater and lesser sensitivity to KDM5 inhibition respectively. KDM5 inhibition may therefore be an effective therapeutic strategy for ameliorating KMT2D loss of function mutations in malignancies such as germinal centre lymphomas.

2021-06-01 | GSE114492 | GEO

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [2]

2021-06-01 | GSE152642 | GEO

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [1]

Project description:KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [1]

| PRJNA471534 | ENA

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [2]

Project description:KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [2]

| PRJNA639892 | ENA

KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas.

Project description:Loss-of-function mutations in KMT2D are a striking feature of germinal center (GC) lymphomas, resulting in decreased histone 3 lysine 4 (H3K4) methylation and altered gene expression. We hypothesized that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would reestablish H3K4 methylation and restore the expression of genes repressed on loss of KMT2D. KDM5 inhibition increased H3K4me3 levels and caused an antiproliferative response in vitro, which was markedly greater in both endogenous and gene-edited KMT2D mutant diffuse large B-cell lymphoma cell lines, whereas tumor growth was inhibited in KMT2D mutant xenografts in vivo. KDM5 inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signaling and altered expression of B-cell lymphoma 2 (BCL2) family members, including BCL2 itself. KDM5 inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC lymphomas.

| S-EPMC8351530 | biostudies-literature

Targeting Lysine Demethylase 5 (KDM5) in Mantle Cell Lymphoma

Project description:Loss of function mutations in the histone methyltransferase KMT2D are common in lymphomas but difficult to target. We reported targeting KDM5 restores epigenetic balance in germinal centre (GC) lymphomas. Here, we show the KDM5 family are over-expressed in mantle cell lymphoma (MCL). GS716054, a pro-drug, increases H3K4 trimethylation (H3K4me3) and kills MCL cells including TP53 mutated cells via suppression of the MYC pathway. It can overcome ibrutinib resistance and synergises with ibrutinib. These data suggest a possible role for KDM5-inhibitors in advanced MCL.

2024-09-24 | GSE243395 | GEO

Targeting KDM6A-KMT2D-p300 axis as a therapeutic strategy for diverse coronaviruses [RNAseq]

Project description:Targeting KDM6A-KMT2D-p300 axis as a therapeutic strategy for diverse coronaviruses [RNAseq]

| PRJNA949173 | ENA

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-06-01 | GSE153671 | GEO

RNA-seq of HER2-positive breast cancer BT474 cell line in response to KDM5 ihibition

Project description:Alterations in the histone methylation profiles are observed in various types of cancer and targeting of this epigenetic process has therapeutic potential. Here we provide proof-of-principle that pharmacological targeting of KDM5 histone-demethylases is a new strategy for the personalized treatment of HER2-positive breast cancer. This analysis demonstrates that cells characterized by HER2-positivity are particularly sensitive to KDM5 inhibition. The results are confirmed in an appropriate in vivo model with a close structural analogue (KDM5-inh1A). In selected HER2-positive breast cancer cells, we demonstrate synergistic interactions between KDM5-inh1 and HER2-targeting agents (trastuzumab and lapatinib). In addition, HER2-positive cell lines showing innate/acquired resistance to trastuzumab show sensitivity to KDM5-inh1. The levels of KDM5A/B/C proteins, which are selectively targeted by the agent, have no significant association with KDM5-inh1 responsiveness across our panel of breast cancer cell lines, suggesting the existence of other determinants of sensitivity. Using RNA-sequencing data of the breast cancer cell lines, we generate a gene-expression model, consisting of fifteen genes, which is a robust predictor of KDM5-inh1 sensitivity. In a test set of breast cancers, this model correctly predicts sensitivity to the compound in a large fraction of HER2+ tumors. In conclusion, KDM5 inhibition has potential in the treatment of HER2+ breast cancer and our gene-expression model can be developed into a diagnostic tool to select patients who may benefit from treatments based on KDM5-inhibitors.

2019-02-01 | E-MTAB-7433 | biostudies-arrayexpress

Comparative gene expression analysis in OCI-LY19 isogenic cell lines with SETD1B mutation or KMT2D+SETD1B double mutants.

Project description:The translocation t(14;18) activates BCL2 and is considered the initiating genetic lesion in most follicular lymphomas (FL). Surprisingly, FL patients fail to respond to the BCL2 inhibitor, Venetoclax. We show that mutations and deletions affecting the histone lysine methyltransferase SETD1B (KMT2G) occur in 7% of FLs and in 16% of diffuse large B cell lymphomas (DLBCL). Deficiency in SETD1B confers striking resistance to Venetoclaxand to an experimental MCL-1 inhibitor. SETD1B also acts as a tumor suppressor andcooperates with loss ofKMT2Din lymphoma development in vivo. Consistently, loss of SETD1B in human lymphomas typically coincides with loss of KMT2D. Mechanistically, SETD1B is required for the expression of several pro-apoptotic BCL2 family proteins. Conversely, inhibitors of the KDM5 histoneH3K4demethylases restore BIM and BIK expression and synergize with Venetoclax inSETD1B-deficient lymphomas.

2024-08-23 | GSE273152 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data