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| Status |
Public on Jul 08, 2022 |
| Title |
Evaluation of the synergistic potential of simultaneous pan- or isoform specific BET and SYK inhibition in B-cell lymphoma (microarray) |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
Comparative expression analyses of AZD+Ento exposed SU-DHL-4 and DG-75 cells compared to DMSO control and AZD or Ento single agents; all sample measured in three biological triplicates
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| Contributor(s) |
Sender S, Sultan AW, Palmer D, Koczan D, Sekora A, Beck J, Schuetz E, Brenig B, Fuellen G, Junghanss C, Escobar HM |
| Citation missing |
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| Submission date |
Jul 01, 2022 |
| Last update date |
Aug 31, 2022 |
| Contact name |
Sina Sender |
| E-mail(s) |
[email protected]
|
| Organization name |
Rostock University Medical Center
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| Department |
Department of Medicine, Clinic III
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| Lab |
Hematology/Oncology
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| Street address |
Schillingallee 70
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| City |
Rostock |
| State/province |
Mecklenburg Vorpommern |
| ZIP/Postal code |
18059 |
| Country |
Germany |
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| Platforms (1) |
| GPL23126 |
[Clariom_D_Human] Affymetrix Human Clariom D Assay [transcript (gene) version] |
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| Samples (24)
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| This SubSeries is part of SuperSeries: |
| GSE207383 |
Evaluation of the synergistic potential of simultaneous pan- or isoform specific BET and SYK inhibition in B-cell lymphoma |
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| Relations |
| BioProject |
PRJNA854955 |
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