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CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas

ABSTRACT: CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas

PROVIDER: PRJNA640005 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12033000.fastq.gz	Fastqsanger.gz
	SRR12033001.fastq.gz	Fastqsanger.gz
	SRR12033002.fastq.gz	Fastqsanger.gz
	SRR12033003_1.fastq.gz	Fastqsanger.gz
	SRR12033003_2.fastq.gz	Fastqsanger.gz

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CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_Toledo]

Project description:Somatic mutations affecting CREBBP and EP300 are a hallmark of Diffuse Large B Cell Lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small molecule inhibitors of CARM1 in DLBCL and other cancers.

2020-06-18 | GSE152667 | GEO

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_MEF]

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CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [ChIP-seq]

2020-06-18 | GSE152665 | GEO

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_MEF]

Project description:CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_MEF]

| PRJNA640009 | ENA

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [ChIP-seq]

Project description:CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [ChIP-seq]

| PRJNA640008 | ENA

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_Toledo]

Project description:CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas [RNA-seq_Toledo]

| PRJNA640010 | ENA

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas.

Project description:Somatic mutations affecting CREBBP and EP300 are a hallmark of diffuse large B-cell lymphoma (DLBCL). These mutations are frequently monoallelic, within the histone acetyltransferase (HAT) domain and usually mutually exclusive, suggesting that they might affect a common pathway, and their residual WT expression is required for cell survival. Using in vitro and in vivo models, we found that inhibition of CARM1 activity (CARM1i) slows DLBCL growth, and that the levels of sensitivity are positively correlated with the CREBBP/EP300 mutation load. Conversely, treatment of DLBCLs that do not have CREBBP/EP300 mutations with CARM1i and a CBP/p300 inhibitor revealed a strong synergistic effect. Our mechanistic data show that CARM1i further reduces the HAT activity of CBP genome wide and downregulates CBP-target genes in DLBCL cells, resulting in a synthetic lethality that leverages the mutational status of CREBBP/EP300 as a biomarker for the use of small-molecule inhibitors of CARM1 in DLBCL and other cancers.

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Expression data from WT, Crebbp+/- and Ep300+/- bone marrow stroma

Project description:We found that the bone marrow microenvironment of Crebbp+/- mice was unable to properly maintain the immature stem - and progenitor pools. Instead, it stimulates myeloid differentiation that progresses into a myeloproliferative-like disease. Since CREBBP is a transcriptional co-activator, we used gene expression analysis to globally assess functional deficiencies in Crebbp+/- bone marrow stroma cells at a molecular level. Ep300 encodes a protein which is highly similar in structure and function to CREBBP; nevertheless, Ep300+/- mice suffer neither excessive myeloid differentiation nor loss of HSCs. Therefore, to identify expression changes specifically related to Crebbp heterozygosity, we focused on genes that showed significant differences in expression levels between Crebbp+/- and wild-type bone marrow stroma but no difference between Ep300+/- and wild-type. Bone marrow stroma was established from wild-type, Crebbp+/- and Ep300+/- mice that were 3-4 months old for RNA extraction and hybridization on Affymetrix microarrays. There are 4 biological replicates for each genotype used.

2011-03-01 | E-GEOD-24773 | biostudies-arrayexpress

CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300 mutated lymphomas

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

2020-06-18 | GSE152668 | GEO

Targeting CREBBP/EP300 bromodomains in cancer

Project description:Changes in gene expression caused by CREBBP/EP300 bromodomain inhibitors in a CML cell line

2018-06-12 | GSE110229 | GEO