Transcriptomic profiling in canine B-cell lymphoma supports a synergistic effect of BTK and PI3K inhibitors
IntroductionB-cell receptor (BCR) signaling has revealed itself as a critical pathway in the pathogenesis of B-cell lymphoma. Within this pathway, the inhibition of Bruton's tyrosine kinase (BTK) or Phosphoinositide 3-kinases (PI3Ks) alone presents encouraging efficacy in the treatment of certa...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Veterinary Science |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fvets.2025.1577028/full |
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| author | Xenia Lainscsek Weibo Kong Barbara C. Rütgen Julia Beck Bertram Brenig Ingo Nolte Hugo Murua Escobar Hugo Murua Escobar Leila Taher Leila Taher |
| author_facet | Xenia Lainscsek Weibo Kong Barbara C. Rütgen Julia Beck Bertram Brenig Ingo Nolte Hugo Murua Escobar Hugo Murua Escobar Leila Taher Leila Taher |
| author_sort | Xenia Lainscsek |
| collection | DOAJ |
| description | IntroductionB-cell receptor (BCR) signaling has revealed itself as a critical pathway in the pathogenesis of B-cell lymphoma. Within this pathway, the inhibition of Bruton's tyrosine kinase (BTK) or Phosphoinositide 3-kinases (PI3Ks) alone presents encouraging efficacy in the treatment of certain both canine and human hematological malignancies.MethodsHere we characterized the effects of the BTK inhibitor Ibrutinib and the PI3K inhibitor AS-605240 as single and combined agents in the canine pre-clinical diffuse large B cell lymphoma (DLBCL) model CLBL-1 by assaying cell proliferation and metabolic activity, and performing RNA-seq to measure gene expression changes.ResultsWe found 2,336 differentially expressed genes (DEGs) across all treatment types and time points relative to the control. The largest number of DEGs were induced by the combination of Ibrutinib and AS-605240. These genes were involved in adaptive immune response, leukotriene D4 metabolic and terms related to regulation of GTP and GTPase mediated signal transduction. Weighted gene co-expression network analysis (WGCNA) detected nine gene modules, five of which were associated with treatment response. Eighteen-percent of genes within these modules were also differentially expressed. Notably, we observed one module that was exclusively associated with the combined treatment whose gene members were related to cellular metabolism, homeostasis signaling, and protein synthesis and regulation.ConclusionNarrowing in on highly connected genes of modules associated with treatment response with large fold changes across treatments which play roles in the main targeted pathways identified PAG1, PRKAR2A, ACACA, FOS, and PRKCA as potential primary candidates of the synergistic treatment effect. |
| format | Article |
| id | doaj-art-89d2df8e5dc3469c8da684b66beca992 |
| institution | DOAJ |
| issn | 2297-1769 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Veterinary Science |
| spelling | doaj-art-89d2df8e5dc3469c8da684b66beca9922025-08-20T03:13:51ZengFrontiers Media S.A.Frontiers in Veterinary Science2297-17692025-04-011210.3389/fvets.2025.15770281577028Transcriptomic profiling in canine B-cell lymphoma supports a synergistic effect of BTK and PI3K inhibitorsXenia Lainscsek0Weibo Kong1Barbara C. Rütgen2Julia Beck3Bertram Brenig4Ingo Nolte5Hugo Murua Escobar6Hugo Murua Escobar7Leila Taher8Leila Taher9Institute of Biomedical Informatics, Graz University of Technology, Graz, AustriaClinic for Hematology, Oncology and Palliative Care, Rostock University Medical Center, University of Rostock, Rostock, GermanyDepartment for Pathobiology, Clinical Pathology, University of Veterinary Medicine Vienna, Vienna, AustriaChronix Biomedical GmbH, Göttingen, GermanyInstitute of Veterinary Medicine, University of Göttingen, Göttingen, GermanySmall Animal Clinic, University of Veterinary Medicine Hannover, Hannover, GermanyClinic for Hematology, Oncology and Palliative Care, Rostock University Medical Center, University of Rostock, Rostock, GermanyInstitute of Medical Genetics, Rostock University Medical Center, University of Rostock, Rostock, GermanyInstitute of Biomedical Informatics, Graz University of Technology, Graz, AustriaInstitute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, University of Rostock, Rostock, GermanyIntroductionB-cell receptor (BCR) signaling has revealed itself as a critical pathway in the pathogenesis of B-cell lymphoma. Within this pathway, the inhibition of Bruton's tyrosine kinase (BTK) or Phosphoinositide 3-kinases (PI3Ks) alone presents encouraging efficacy in the treatment of certain both canine and human hematological malignancies.MethodsHere we characterized the effects of the BTK inhibitor Ibrutinib and the PI3K inhibitor AS-605240 as single and combined agents in the canine pre-clinical diffuse large B cell lymphoma (DLBCL) model CLBL-1 by assaying cell proliferation and metabolic activity, and performing RNA-seq to measure gene expression changes.ResultsWe found 2,336 differentially expressed genes (DEGs) across all treatment types and time points relative to the control. The largest number of DEGs were induced by the combination of Ibrutinib and AS-605240. These genes were involved in adaptive immune response, leukotriene D4 metabolic and terms related to regulation of GTP and GTPase mediated signal transduction. Weighted gene co-expression network analysis (WGCNA) detected nine gene modules, five of which were associated with treatment response. Eighteen-percent of genes within these modules were also differentially expressed. Notably, we observed one module that was exclusively associated with the combined treatment whose gene members were related to cellular metabolism, homeostasis signaling, and protein synthesis and regulation.ConclusionNarrowing in on highly connected genes of modules associated with treatment response with large fold changes across treatments which play roles in the main targeted pathways identified PAG1, PRKAR2A, ACACA, FOS, and PRKCA as potential primary candidates of the synergistic treatment effect.https://www.frontiersin.org/articles/10.3389/fvets.2025.1577028/fullcanine lymphomatyrosine kinase inhibitorsphosphoinositide 3-kinase inhibitorsRNA-seqdifferential expression analysisco-expression network analysis |
| spellingShingle | Xenia Lainscsek Weibo Kong Barbara C. Rütgen Julia Beck Bertram Brenig Ingo Nolte Hugo Murua Escobar Hugo Murua Escobar Leila Taher Leila Taher Transcriptomic profiling in canine B-cell lymphoma supports a synergistic effect of BTK and PI3K inhibitors Frontiers in Veterinary Science canine lymphoma tyrosine kinase inhibitors phosphoinositide 3-kinase inhibitors RNA-seq differential expression analysis co-expression network analysis |
| title | Transcriptomic profiling in canine B-cell lymphoma supports a synergistic effect of BTK and PI3K inhibitors |
| title_full | Transcriptomic profiling in canine B-cell lymphoma supports a synergistic effect of BTK and PI3K inhibitors |
| title_fullStr | Transcriptomic profiling in canine B-cell lymphoma supports a synergistic effect of BTK and PI3K inhibitors |
| title_full_unstemmed | Transcriptomic profiling in canine B-cell lymphoma supports a synergistic effect of BTK and PI3K inhibitors |
| title_short | Transcriptomic profiling in canine B-cell lymphoma supports a synergistic effect of BTK and PI3K inhibitors |
| title_sort | transcriptomic profiling in canine b cell lymphoma supports a synergistic effect of btk and pi3k inhibitors |
| topic | canine lymphoma tyrosine kinase inhibitors phosphoinositide 3-kinase inhibitors RNA-seq differential expression analysis co-expression network analysis |
| url | https://www.frontiersin.org/articles/10.3389/fvets.2025.1577028/full |
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