A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia
Abstract Background About 40% of relapsed or non-responder tumors exhibit therapeutic resistance in the absence of a clear genetic cause, suggesting a pivotal role of intracellular communication. A deeper understanding of signaling pathways rewiring occurring in resistant cells is crucial to propose...
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BMC
2025-04-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02185-0 |
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| author | Valeria Bica Veronica Venafra Giorgia Massacci Simone Graziosi Sara Gualdi Gessica Minnella Federica Sorà Patrizia Chiusolo Maria Elsa Brunetti Gennaro Napolitano Massimo Breccia Dimitrios Mougiakakos Martin Böttcher Thomas Fischer Livia Perfetto Francesca Sacco |
| author_facet | Valeria Bica Veronica Venafra Giorgia Massacci Simone Graziosi Sara Gualdi Gessica Minnella Federica Sorà Patrizia Chiusolo Maria Elsa Brunetti Gennaro Napolitano Massimo Breccia Dimitrios Mougiakakos Martin Böttcher Thomas Fischer Livia Perfetto Francesca Sacco |
| author_sort | Valeria Bica |
| collection | DOAJ |
| description | Abstract Background About 40% of relapsed or non-responder tumors exhibit therapeutic resistance in the absence of a clear genetic cause, suggesting a pivotal role of intracellular communication. A deeper understanding of signaling pathways rewiring occurring in resistant cells is crucial to propose alternative effective strategies for cancer patients. Methods To achieve this goal, we developed a novel multi-step strategy, which integrates high sensitive mass spectrometry-based phosphoproteomics with network-based analysis. This strategy builds context-specific networks recapitulating the signaling rewiring upon drug treatment in therapy-resistant and sensitive cells. Results We applied this strategy to elucidate the BCR::ABL1-independent mechanisms that drive relapse upon therapy discontinuation in chronic myeloid leukemia (CML) patients. We built a signaling map, detailing - from receptor to key phenotypes - the molecular mechanisms implicated in the control of proliferation, DNA damage response and inflammation of therapy-resistant cells. In-depth analysis of this map uncovered novel therapeutic vulnerabilities. Functional validation in patient-derived leukemic stem cells revealed a crucial role of acquired FLT3-dependency and its underlying molecular mechanism. Conclusions In conclusion, our study presents a novel generally applicable strategy and the reposition of FLT3, one of the most frequently mutated drivers of acute leukemia, as a potential therapeutic target for CML relapsed patients. |
| format | Article |
| id | doaj-art-00c843e6d0934990ab3bb953d57a2b38 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-00c843e6d0934990ab3bb953d57a2b382025-08-20T03:52:24ZengBMCCell Communication and Signaling1478-811X2025-04-0123111710.1186/s12964-025-02185-0A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemiaValeria Bica0Veronica Venafra1Giorgia Massacci2Simone Graziosi3Sara Gualdi4Gessica Minnella5Federica Sorà6Patrizia Chiusolo7Maria Elsa Brunetti8Gennaro Napolitano9Massimo Breccia10Dimitrios Mougiakakos11Martin Böttcher12Thomas Fischer13Livia Perfetto14Francesca Sacco15Ph.D. Program in Cellular and Molecular Biology, Department of Biology, University of Rome ’Tor Vergata’Ph.D. Program in Cellular and Molecular Biology, Department of Biology, University of Rome ’Tor Vergata’Department of Biology, University of Rome Tor VergataPh.D. Program in Cellular and Molecular Biology, Department of Biology, University of Rome ’Tor Vergata’Department of Biology and Biotechnologies “C. Darwin”, University of Rome La SapienzaSezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro CuoreSezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro CuoreSezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro CuoreTelethon Institute of Genetics and Medicine (TIGEM)Telethon Institute of Genetics and Medicine (TIGEM)Department of Translational and Precision Medicine, Azienda Policlinico Umberto I, Sapienza University of RomeHealth campus for Inflammation, Immunity and Infection (GCI3), University of MagdeburgHealth campus for Inflammation, Immunity and Infection (GCI3), University of MagdeburgHealth campus for Inflammation, Immunity and Infection (GCI3), University of MagdeburgDepartment of Biology and Biotechnologies “C. Darwin”, University of Rome La SapienzaDepartment of Biology, University of Rome Tor VergataAbstract Background About 40% of relapsed or non-responder tumors exhibit therapeutic resistance in the absence of a clear genetic cause, suggesting a pivotal role of intracellular communication. A deeper understanding of signaling pathways rewiring occurring in resistant cells is crucial to propose alternative effective strategies for cancer patients. Methods To achieve this goal, we developed a novel multi-step strategy, which integrates high sensitive mass spectrometry-based phosphoproteomics with network-based analysis. This strategy builds context-specific networks recapitulating the signaling rewiring upon drug treatment in therapy-resistant and sensitive cells. Results We applied this strategy to elucidate the BCR::ABL1-independent mechanisms that drive relapse upon therapy discontinuation in chronic myeloid leukemia (CML) patients. We built a signaling map, detailing - from receptor to key phenotypes - the molecular mechanisms implicated in the control of proliferation, DNA damage response and inflammation of therapy-resistant cells. In-depth analysis of this map uncovered novel therapeutic vulnerabilities. Functional validation in patient-derived leukemic stem cells revealed a crucial role of acquired FLT3-dependency and its underlying molecular mechanism. Conclusions In conclusion, our study presents a novel generally applicable strategy and the reposition of FLT3, one of the most frequently mutated drivers of acute leukemia, as a potential therapeutic target for CML relapsed patients.https://doi.org/10.1186/s12964-025-02185-0Chronic myeloid leukemiaBCR:ABL1-independent resistanceSignaling pathwaysPhosphoproteomicsComputational strategyDrug repurposing |
| spellingShingle | Valeria Bica Veronica Venafra Giorgia Massacci Simone Graziosi Sara Gualdi Gessica Minnella Federica Sorà Patrizia Chiusolo Maria Elsa Brunetti Gennaro Napolitano Massimo Breccia Dimitrios Mougiakakos Martin Böttcher Thomas Fischer Livia Perfetto Francesca Sacco A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia Cell Communication and Signaling Chronic myeloid leukemia BCR:ABL1-independent resistance Signaling pathways Phosphoproteomics Computational strategy Drug repurposing |
| title | A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia |
| title_full | A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia |
| title_fullStr | A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia |
| title_full_unstemmed | A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia |
| title_short | A network-based approach to overcome BCR::ABL1-independent resistance in chronic myeloid leukemia |
| title_sort | network based approach to overcome bcr abl1 independent resistance in chronic myeloid leukemia |
| topic | Chronic myeloid leukemia BCR:ABL1-independent resistance Signaling pathways Phosphoproteomics Computational strategy Drug repurposing |
| url | https://doi.org/10.1186/s12964-025-02185-0 |
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