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Targeting AURKA to induce synthetic lethality in CREBBP-deficient DLBCL via attenuation of MYC expression

ABSTRACT: Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in diffuse large B-cell lymphoma (DLBCL), highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic DLBCL cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk DLBCL harboring CREBBP inactivating mutations. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for CREBBP and H3K27ac in SC1 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232330 | GEO | 2025/05/13

REPOSITORIES: GEO

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Targeting AURKA to induce synthetic lethality in CREBBP-deficient DLBCL via attenuation of MYC expression

Project description:Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in diffuse large B-cell lymphoma (DLBCL), highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic DLBCL cell models, we demonstrated that CREBBP deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk DLBCL harboring CREBBP inactivating mutations.

2025-05-13 | GSE211451 | GEO

Targeting AURKA to induce synthetic lethality in CREBBP-deficient DLBCL via attenuation of MYC expression

Project description:Targeting AURKA to induce synthetic lethality in CREBBP-deficient DLBCL via attenuation of MYC expression

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Targeting AURKA to induce synthetic lethality in CREBBP-deficient DLBCL via attenuation of MYC expression

Project description:Targeting AURKA to induce synthetic lethality in CREBBP-deficient DLBCL via attenuation of MYC expression

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CREBBP cooperates with cell cycle machinery to attenuate chidamide sensitivity in relapsed/refractory DLBCL

Project description:Frequent inactivating mutations of histone acetyltransferase CREBBP is a characteristic feature of diffuse large B-cell lymphoma (DLBCL), highlighting the attractiveness of targeting the CREBBP deficiency as a therapeutic strategy. In this study, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating a subgroup of relapsed/refractory DLBCL patients, achieving an overall response rate (ORR) of 25.0% and a complete response (CR) rate of 15.0%. However, the clinical response to chidamide remains poor as most patients exhibit resistance, hampering the clinical utility of the drug. Functional studies in both in vitro and in vivo models showed that CREBBP loss of function is correlated with chidamide sensitivity, which is associated with modulating cell cycle machinery. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators identified AURKA inhibitors, which inhibited G2/M transition during cell cycling, as top candidates that synergistically enhanced antitumor effects of chidamide in CREBBP-proficient DLBCL cells. Our study demonstrated that CREBBP inactivation can serve as a potential biomarker to predict chidamide sensitivity, while a combination of AURKA inhibitor and chidamide provides a novel therapeutic strategy for the treatment of relapsed/refractory DLBCL.

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H3K27Ac mapping in isogenic CREBBP-WT, CREBBP-KO and EP300-KO SUDHL4 cell lines

Project description:Inactivating mutations of the CREBBP acetyltransferase and, at lower frequencies, its paralogue EP300 are among the most common genetic alterations in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most frequent B cell malignancies. Here we uncover unexpected distinct functions for CREBBP and EP300 in the germinal center (GC), i.e. the target structure for most human B cell lymphomas. We show that these proteins modulate non-overlapping transcriptional programs that are preferentially enriched in biological functions associated with the separate anatomic compartments of the GC. Consistently, deletion of CREBBP or EP300 have opposing effects on GC formation in vivo. Nonetheless, these proteins partially compensate for each other to maintain a minimal threshold of acetyltransferase activity and guarantee homeostatic control of the GC, which is completely abrogated by their combined loss. This synthetic lethal interaction is retained in DLBCL cells, identifying an Achille’s heel in CREBBP-mutant lymphomas that could be pharmacologically targeted by using a novel, selective small molecule inhibitor of the CREBBP/EP300 bromodomain. These data shed light on the unique roles of CREBBP and EP300 in the physiology and pathology of GC B cells, and provide a proof-of-principle for the development and testing of EP300 inhibition as a therapeutic strategy in these diseases.

2020-02-19 | GSE132365 | GEO

Identification of CREBBP bound genes in germinal center B cells

Project description:Inactivating mutations of the gene encoding for the CREBBP acetyltransferase are highly frequent in diffuse large B cell lymphoma (DLBCL, 30% of cases) and follicular lymphoma (FL, 60% of cases), the two most common cancers derived from the germinal-center (GC). However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Using functional epigenomics and mouse genetics, here we define the program modulated by CREBBP in primary human GC B cells and show that CREBBP regulates enhancer/super-enhancer networks, with specific roles in GC/post-GC cell fate decisions. Conditional GC-specific deletion of Crebbp in the mouse perturbs the expression of a limited set of genes involved in the regulation of signal transduction (BCR, TLR and CD40), lineage specification (NF-κB and BCL6) and terminal B cell differentiation (PRDM1, IRF4). Consistently, Crebbp-deficient B cells exhibit proliferative advantage and show impaired plasma cell differentiation. While GC-specific loss of Crebbp was not sufficient to initiate malignant transformation, compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics ofFL and DLBCL, display an increased incidence of clonal lymphoid malignancies recapitulating the features of the human diseases. These findings establish CREBBPas a haploinsufficient tumor suppressor gene in GC B cells and provide insights into the mechanisms and targets by which loss of CREBBP contributes to lymphomagenesis.

2017-01-11 | GSE89688 | GEO

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

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 | GSE152665 | GEO

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

2020-06-18 | GSE152667 | GEO

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

2020-06-18 | GSE152666 | GEO

Transcriptome profiling (RNA-seq) of CREBBP+/+ and CREBBP+/- clones of U2932 DLBCL cell line

Project description:Purpose: Diffuse large B cell lymphomas (DLBCL) frequently harbor mutations in the histone acetyltransferase CREBBP, however their functional contribution to lymphomagenesis remains largely unknown. This study aims at elucidating and characterizing the molecular pathways affected by mutations in CREBBP. Methods: U2932, a DLBCL cell line that has wild type expression of CREBBP was manipulated by CRISPR-Cas9 strategy to mutate one allele of CREBBP and examine the pathways affected. RNA was isolated using the NucleoSping RNA Kit (Macherey-Nagel) from five wild type (CREBBP+/+) and five heterozygous clones (CREBBP+/-). RNA quality was assessed by Bioanalyzer 2100 followed by library preparation using the TruSeq RNA Sample Prep Kit v4 (Illumina). Sequencing was subsequently performed on the Illumina HiSeq 2500 instrument. RNA-seq reads were quality-checked with fastqc, which computes various quality metrics for the raw reads. RNA-seq reads were mapped to the GRCh38 reference human genome using STAR and reads were counted according to Ensembl gene annotation using the featureCounts function in the Rsubread Bioconductor package. Statistical analysis of differential expression was conducted with the DESeq2 package.

2016-11-16 | GSE89879 | GEO

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