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Evaluation of the synergistic potential of simultaneous pan- or isoform specific BET and SYK inhibition in B-cell lymphoma (microarray)

ABSTRACT: Background: Bromodomain and extra-terminal domain (BET) proteins and the spleen tyrosine kinase (SYK) represent promising targets in Diffuse large B-cell (DLBCL) and Burkitt’s lymphoma (BL). We evaluated the anti-lymphoma activity of the isoform specific bivalent BET inhibitor AZD5153 (AZD) and the pan-BET inhibitor I-BET151 (I-BET) as single agents and in combination with SYK inhibitor Entospletinib in vitro. Methods: Single agent exposures were evaluated on two DLBCL and two BL cell lines analyzing cell proliferation and metabolic activity. Proliferation, metabolic activity, apoptosis, cell cycle and morphology were investigated after combined AZD or I-BET and Ento exposure. RNAseq of combined AZD+Ento exposure was characterized in SU-DHL-4. Background: Bromodomain and extra-terminal domain (BET) proteins and the spleen tyrosine kinase (SYK) represent promising targets in Diffuse large B-cell (DLBCL) and Burkitt’s lymphoma (BL). We evaluated the anti-lymphoma activity of the isoform specific bivalent BET inhibitor AZD5153 (AZD) and the pan-BET inhibitor I-BET151 (I-BET) as single agents and in combination with SYK inhibitor Entospletinib in vitro. Methods: Single agent exposures were evaluated on two DLBCL and two BL cell lines analyzing cell proliferation and metabolic activity. Proliferation, metabolic activity, apoptosis, cell cycle and morphology were investigated after combined AZD or I-BET and Ento exposure. RNAseq of combined AZD+Ento exposure was characterized in SU-DHL-4. Results: Both BET inhibitors reduced cell proliferation/metabolic activity dose and time de-pendently. Combined BET and SYK inhibition enhanced the anti-proliferative effect and induc-ing a G0/G1 cell cycle arrest. SU-DHL-4 demonstrated a pronounced modulation of gene expres-sion by AZD, which was markedly increased by additional SYK inhibition. Functional enrich-ment analyses identified combination-specific GO terms related to cell division, transport and DNA replication. Genes such as PLEKHH3, MYB, SLC8A1, PARP9, HSPB1 and S100A4 were iden-tified as the presumable key regulators. Conclusion: Simultaneous inhibition of BET and SYK enhanced the anti-proliferative effects, and especially the combination-specific gene expression signature.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207381 | GEO | 2022/07/08

REPOSITORIES: GEO

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Project description:We studied transcriptional changes by Affymetrix human microarrays in DLBCL cell lines as a result of treatment with GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2 In eukaryotes, epigenetic post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and is responsible for repressing target gene expression through methylation of histone H3 on lysine 27 (H3K27). Over-expression of EZH2 is implicated in tumorigenesis and correlates with poor prognosis in multiple tumor types. Recent reports have identified somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The Y641 residue is the most frequently mutated residue, with 22% of GCB (Germinal Cell B-cell) DLBCL and FL harboring mutations at this site. These lymphomas exhibit increased H3K27 tri-methylation (H3K27me3) due to altered substrate preferences of the mutant enzymes. However, it is unknown whether direct inhibition of EZH2 methyltransferase activity alone will be effective in treating lymphomas carrying activating EZH2 mutations. Herein, we demonstrate that GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and dramatically inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma. 10 DLBCL cell lines (7 mutant and 3 wild type EZH2), that were differentially sensitive to GSK126 in proliferation assays, were treated for 72 hours, in duplicate (n=2), with either DMSO (vehicle) or 500nM of GSK126, a potent selective EZH2 inhibitor. EZH2 mutant cell lines are Pfeiffer, KARPAS-422, WSU-DLCL2, SU-DHL-10, SU-DHL-6, DB and SU-DHL-4. EZH2 wildtype cell lines are HT, OCI-LY-19 and Toledo.

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Evaluation of the synergistic potential of simultaneous pan- or isoform specific BET and SYK inhibition in B-cell lymphoma (microarray)

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