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Characterisation of the anti-lymphoma activity of pracinostat reveals differential sensitivities of DLBCL cells to HDAC inhibitors

ABSTRACT: Characterisation of the anti-lymphoma activity of pracinostat reveals differential sensitivities of DLBCL cells to HDAC inhibitors

PROVIDER: PRJNA636641 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11906500_1.fastq.gz	Fastqsanger.gz
	SRR11906500_2.fastq.gz	Fastqsanger.gz
	SRR11906501_1.fastq.gz	Fastqsanger.gz
	SRR11906501_2.fastq.gz	Fastqsanger.gz
	SRR11906502_1.fastq.gz	Fastqsanger.gz

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Characterisation of the anti-lymphoma activity of pracinostat reveals differential sensitivities of DLBCL cells to HDAC inhibitors

Project description:6 lymphoma cell lines (OCILY1, SUDHL4, TOLEDO, WSUDLCL2, PFEIFFER, SUDHL6) have been treated with DMSO, Vorinostat and Pracinostat. The transcriptome has been sequenced after 6hrs and 14 days from the treatment. The gene expression levels have been compared in order to elucidate the differencies and similarities for Vorinostat and Pracinostat compare to DMSO (control group).

2021-06-02 | GSE151612 | GEO

Interactome of Aiolos/Ikaros Reveals Combination Rationale of Cereblon Modulators with HDAC Inhibitors in DLBCL

Project description:Purpose: Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of the small molecules lenalidomide (Len) and avadomide (Ava). Upon binding of the drugs, Aiolos and Ikaros are recruited to the E3 ligase, ubiquitylated and subsequently degraded. In DLBCL cells, Aiolos and Ikaros are direct transcriptional repressors of interferon stimulated genes (ISG) and degradation of these substrates results in increased ISG protein levels resulting in decreased proliferation and apoptosis. Herein, we aimed to uncover the mechanism(s) Aiolos and Ikaros use to repress ISG transcription and provide a mechanistic rationale for a combination strategy enhance cell autonomous activites of CELMoDs. Results: We describe that in DLBCL, the repression of ISG transcription is accomplished in part through recruitment of large transcriptional complexes such as the nucleosome remodeling and deacetylase (NuRD) which modify the chromatin landscape of these promoters. A rational combination approach of Ava with a specific HDAC inhibitor leads to a significant increase in ISG transcription compared to either single agent, and synergistic antiproliferative activity in DLBCL cell lines. Conclusion: Our results provide a novel role for lineage factors Aiolos and Ikaros in DLBCL as well as further insight into the mechanism(s) of Aiolos and Ikaros mediated transcriptional repression and unique therapeutic combination strategies.

2022-07-12 | GSE201324 | GEO

Study of the antilymphoma activity of pracinostat reveals different sensitivities of DLBCL cells to HDAC inhibitors.

Project description:Histone deacetylase inhibitors (HDACis) are antitumor agents with distinct efficacy in hematologic tumors. Pracinostat is a pan-HDACi with promising early clinical activity. However, similar to other HDACis, its activity as a single agent is limited. Diffuse large B-cell lymphoma (DLBCL) includes distinct molecular subsets or metabolically defined subtypes that rely in different ways on the B-cell receptor signaling pathway, oxidative phosphorylation, and glycolysis for their survival. The antitumor activity of pracinostat has not been determined in lymphomas. We performed preclinical in vitro activity screening of 60 lymphoma cell lines that included 25 DLBCLs. DLBCL cells belonging to distinct metabolic subtypes were treated with HDACis for 6 hours or 14 days followed by transcriptional profiling. DLBCL xenograft models enabled assessment of the in vivo antilymphoma activity of pracinostat. Combination treatments with pracinostat plus 10 other antilymphoma agents were performed. Western blot was used to assess acetylation levels of histone and nonhistone proteins after HDACi treatment. Robust antiproliferative activity was observed across all lymphoma histotypes represented. Focusing on DLBCL, we identified a low-sensitivity subset that almost exclusively consists of the oxidative phosphorylation (OxPhos)-DLBCL metabolic subtype. OxPhos-DLBCL cells also showed poorer sensitivity to other HDACis, including vorinostat. Transcriptomic analysis revealed fewer modulated transcripts but an enrichment of antioxidant pathway genes after HDACi treatment of OxPhos-DLBCLs compared with high-sensitivity B-cell receptor (BCR)-DLBCLs. Pharmacologic inhibition of antioxidant production rescued sensitivity of OxPhos-DLBCLs to pracinostat whereas BCR-DLBCLs were unaffected. Our study provides novel insights into the antilymphoma activity of pracinostat and identifies a differential response of DLBCL metabolic subtypes to HDACis.

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Inhibitors of Bcl-2 and Bruton’s tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma (DLBCL) growth

Project description:Methods: DLBCL cell lines RIVA, U-2932 and OCI-LY3 were treated in vitro with ibrutinib (Ibru) or dimethyl sulfoxide (DMSO). Additionally, RIVA and U-2932 were orthotopically transplanted into MISTRG mice and mice were treated for two weeks with Ibru or vehicle. Tumor cells were isolated from the bone marrow at the study endpoint. The total RNA was isolated and the mRNA profiles were generated by next-generation sequencing using the Illumina TruSeq mRNA stranded protocol. Results: We have combined single and combinatorial drug response profiling to show that the combined inhibition of the anti-apoptotic protein Bcl-2 and of the tyrosine kinase BTK with the small molecules venetoclax and ibrutinib efficiently kills DLBCL cells. High Bcl-2 expression due to either BCL2 amplifications or translocations, in conjunction with chronic active BCR signalling accurately predict responses to dual Bcl-2/BTK inhibition.The combined data show that drug sensitivities exposed by drug response profiling can be attributed to specific mutational signatures and immunohistochemical biomarkers, and point to combined Bcl-2/BTK inhibition as a novel promising therapeutic strategy in DLBCL.

2022-01-24 | GSE171763 | GEO

Differentiation of DLBCL induced by HDAC inhibitors is associated with sensitization to proteasome inhibition

Project description:Epigenetic modifying enzymes are commonly mutated in diffuse large B cell lymphoma (DLBCL), suggesting that epigenetic regulation is an important factor in DLBCL pathogenesis and a potential target for therapy. We developed resistant cell lines to histone deacetylase inhibitors (HDACi), one such epigenetic therapy, in order to define mechanisms of response and resistance. Strikingly, using gene expression and metabolic profiling, we found that development of HDACi resistance was associated with differentiation toward a plasmablast-like phenotype. Differentiation correlated with decreased B cell receptor signaling, increased ER stress and activation of the unfolded protein response, and increased sensitivity to proteasome inhibitors. Importantly, we found evidence of differentiation in lymphoma biopsies from patients treated with HDACi. Together, these data show, for the first time, that HDACi are differentiating agents in lymphoma and may be used to prime DLBCL for targeted therapy including proteasome inhibitors. Gene expression in DLBCL cells from tumor biopsies after 15 days panobinostat therapy

2016-08-01 | E-GEOD-59308 | biostudies-arrayexpress

Differentiation of DLBCL induced by HDAC inhibitors is associated with sensitization to proteasome inhibition

2016-08-01 | GSE59308 | GEO

HDAC inhibitors in synovial sarcoma cells

Project description:Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-Seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell cycle arrest, neuronal differentiation and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb-group targets were reactivated including tumor suppressor CDKN2A, and pro-apoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and pro-apoptotic factors BIK, BIM and BMF were important to apoptosis induction following HDAC-inhibition in synovial sarcoma

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Interactome of Aiolos/Ikaros Reveals Combination Rationale of Cereblon Modulators with HDAC Inhibitors in DLBCL

Project description:Interactome of Aiolos/Ikaros Reveals Combination Rationale of Cereblon Modulators with HDAC Inhibitors in DLBCL

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Molecular characterisation and genetic subclassification of diffuse large B-cell lymphoma (DLBCL) of 74 cases

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