Inflammatory signaling pathways play a role in SYK inhibitor resistant AML
Abstract Trials have shown promising clinical activity of the selective SYK inhibitor entospletinib in patients with high expressing HOXA9/MEIS1 acute leukemias. As the development of resistance mechanisms is a common problem in the use of targeted drugs, we performed a chemical library screen to id...
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Nature Portfolio
2025-04-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-96660-w |
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| author | Sarah Tausch Christina Villinger Gabriela Alexe Daniel J. Urban Min Shen Dominique Jahn Jonas Vischedyk Sebastian Scheich Hubert Serve Matthew D. Hall Kimberly Stegmaier Thomas Oellerich Anjali Cremer |
| author_facet | Sarah Tausch Christina Villinger Gabriela Alexe Daniel J. Urban Min Shen Dominique Jahn Jonas Vischedyk Sebastian Scheich Hubert Serve Matthew D. Hall Kimberly Stegmaier Thomas Oellerich Anjali Cremer |
| author_sort | Sarah Tausch |
| collection | DOAJ |
| description | Abstract Trials have shown promising clinical activity of the selective SYK inhibitor entospletinib in patients with high expressing HOXA9/MEIS1 acute leukemias. As the development of resistance mechanisms is a common problem in the use of targeted drugs, we performed a chemical library screen to identify drug sensitivities in SYK inhibitor resistant AML cells. We identified that SYK inhibitor resistant cells displayed an increased sensitivity to glucocorticoids. Glucocorticoids are potent immunosuppressants which work in part by inhibiting the transcription of cytokine genes. RNA sequencing of entospletinib resistant cells revealed a strong enrichment of inflammatory response and TNFα signaling via NF-κB gene sets in comparison to naive cells. Naive AML cells treated with entospletinib showed a strong downregulation of the same gene sets which were upregulated in the resistant state. Our data suggest that inflammatory signaling pathways play a role in entospletinib resistant AML cells. |
| format | Article |
| id | doaj-art-12f48a8d33da4ab09f09fd148af6232e |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-12f48a8d33da4ab09f09fd148af6232e2025-08-20T03:05:01ZengNature PortfolioScientific Reports2045-23222025-04-0115111110.1038/s41598-025-96660-wInflammatory signaling pathways play a role in SYK inhibitor resistant AMLSarah Tausch0Christina Villinger1Gabriela Alexe2Daniel J. Urban3Min Shen4Dominique Jahn5Jonas Vischedyk6Sebastian Scheich7Hubert Serve8Matthew D. Hall9Kimberly Stegmaier10Thomas Oellerich11Anjali Cremer12Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe UniversityDepartment of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe UniversityDepartment of Pediatric Oncology, Harvard Medical School, Dana-Farber Cancer Institute and Boston Children’s HospitalDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of HealthDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of HealthDepartment of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe UniversityDepartment of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe UniversityDepartment of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe UniversityDepartment of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe UniversityDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of HealthDepartment of Pediatric Oncology, Harvard Medical School, Dana-Farber Cancer Institute and Boston Children’s HospitalDepartment of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe UniversityDepartment of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe UniversityAbstract Trials have shown promising clinical activity of the selective SYK inhibitor entospletinib in patients with high expressing HOXA9/MEIS1 acute leukemias. As the development of resistance mechanisms is a common problem in the use of targeted drugs, we performed a chemical library screen to identify drug sensitivities in SYK inhibitor resistant AML cells. We identified that SYK inhibitor resistant cells displayed an increased sensitivity to glucocorticoids. Glucocorticoids are potent immunosuppressants which work in part by inhibiting the transcription of cytokine genes. RNA sequencing of entospletinib resistant cells revealed a strong enrichment of inflammatory response and TNFα signaling via NF-κB gene sets in comparison to naive cells. Naive AML cells treated with entospletinib showed a strong downregulation of the same gene sets which were upregulated in the resistant state. Our data suggest that inflammatory signaling pathways play a role in entospletinib resistant AML cells.https://doi.org/10.1038/s41598-025-96660-wAcute myeloid leukemia cellsResistanceInflammatory pathwaysGlucocorticoids |
| spellingShingle | Sarah Tausch Christina Villinger Gabriela Alexe Daniel J. Urban Min Shen Dominique Jahn Jonas Vischedyk Sebastian Scheich Hubert Serve Matthew D. Hall Kimberly Stegmaier Thomas Oellerich Anjali Cremer Inflammatory signaling pathways play a role in SYK inhibitor resistant AML Scientific Reports Acute myeloid leukemia cells Resistance Inflammatory pathways Glucocorticoids |
| title | Inflammatory signaling pathways play a role in SYK inhibitor resistant AML |
| title_full | Inflammatory signaling pathways play a role in SYK inhibitor resistant AML |
| title_fullStr | Inflammatory signaling pathways play a role in SYK inhibitor resistant AML |
| title_full_unstemmed | Inflammatory signaling pathways play a role in SYK inhibitor resistant AML |
| title_short | Inflammatory signaling pathways play a role in SYK inhibitor resistant AML |
| title_sort | inflammatory signaling pathways play a role in syk inhibitor resistant aml |
| topic | Acute myeloid leukemia cells Resistance Inflammatory pathways Glucocorticoids |
| url | https://doi.org/10.1038/s41598-025-96660-w |
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