Enlarged PML-nuclear bodies trigger conflicting cell cycle signal-mediated cytotoxicity in leukemia cells
Abstract Accumulating evidence suggests that mitogenic signaling during cell cycle arrest can lead to severe cytotoxic outcomes, such as senescence, though the underlying mechanisms remain poorly understood. Here, we explored the link between cell cycle dynamics and the formation of PML-nuclear bodi...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07911-7 |
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| _version_ | 1849235657722953728 |
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| author | Tomohisa Baba Soichiro Kumamoto Yuta Moriguchi Soji Morishita Atsushi Hirao Yoshikazu Johmura |
| author_facet | Tomohisa Baba Soichiro Kumamoto Yuta Moriguchi Soji Morishita Atsushi Hirao Yoshikazu Johmura |
| author_sort | Tomohisa Baba |
| collection | DOAJ |
| description | Abstract Accumulating evidence suggests that mitogenic signaling during cell cycle arrest can lead to severe cytotoxic outcomes, such as senescence, though the underlying mechanisms remain poorly understood. Here, we explored the link between cell cycle dynamics and the formation of PML-nuclear bodies (PML-NBs), intranuclear structures known to mediate cellular stress responses. Our findings demonstrate that PML-NBs increase their number during interphase arrest. Moreover, the activation of mitogenic ERK signaling by all-trans retinoic acid (ATRA) during CDK4/6 inhibitor-induced cell cycle arrest synergistically enhances the formation of larger PML-NBs by associating with SUMO. This enlargement, triggered by the simultaneous engagement of opposing cell cycle signals, leads to potent cytotoxicity accompanied by either terminal differentiation or apoptosis, depending on the cell type, across multiple acute myeloid leukemia (AML) cell lines. Importantly, in an AML mouse model, this combination treatment significantly improved therapeutic efficacy with minimal effects on normal hematopoiesis. Our results introduce conflicting cell cycle signal-induced cytotoxicity as a promising therapeutic strategy for AML. |
| format | Article |
| id | doaj-art-e4294cb6353e449ca8d69f1c50704dbf |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-e4294cb6353e449ca8d69f1c50704dbf2025-08-20T04:02:44ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111310.1038/s41419-025-07911-7Enlarged PML-nuclear bodies trigger conflicting cell cycle signal-mediated cytotoxicity in leukemia cellsTomohisa Baba0Soichiro Kumamoto1Yuta Moriguchi2Soji Morishita3Atsushi Hirao4Yoshikazu Johmura5Division of Cancer and Senescence Biology, Cancer Research Institute, Kanazawa UniversityDivision of Cancer and Senescence Biology, Cancer Research Institute, Kanazawa UniversityDivision of Cancer and Senescence Biology, Cancer Research Institute, Kanazawa UniversityDepartment of Advanced Hematology, Juntendo University Graduate School of MedicineDivision of Molecular Genetics, Cancer Research Institute, Kanazawa UniversityDivision of Cancer and Senescence Biology, Cancer Research Institute, Kanazawa UniversityAbstract Accumulating evidence suggests that mitogenic signaling during cell cycle arrest can lead to severe cytotoxic outcomes, such as senescence, though the underlying mechanisms remain poorly understood. Here, we explored the link between cell cycle dynamics and the formation of PML-nuclear bodies (PML-NBs), intranuclear structures known to mediate cellular stress responses. Our findings demonstrate that PML-NBs increase their number during interphase arrest. Moreover, the activation of mitogenic ERK signaling by all-trans retinoic acid (ATRA) during CDK4/6 inhibitor-induced cell cycle arrest synergistically enhances the formation of larger PML-NBs by associating with SUMO. This enlargement, triggered by the simultaneous engagement of opposing cell cycle signals, leads to potent cytotoxicity accompanied by either terminal differentiation or apoptosis, depending on the cell type, across multiple acute myeloid leukemia (AML) cell lines. Importantly, in an AML mouse model, this combination treatment significantly improved therapeutic efficacy with minimal effects on normal hematopoiesis. Our results introduce conflicting cell cycle signal-induced cytotoxicity as a promising therapeutic strategy for AML.https://doi.org/10.1038/s41419-025-07911-7 |
| spellingShingle | Tomohisa Baba Soichiro Kumamoto Yuta Moriguchi Soji Morishita Atsushi Hirao Yoshikazu Johmura Enlarged PML-nuclear bodies trigger conflicting cell cycle signal-mediated cytotoxicity in leukemia cells Cell Death and Disease |
| title | Enlarged PML-nuclear bodies trigger conflicting cell cycle signal-mediated cytotoxicity in leukemia cells |
| title_full | Enlarged PML-nuclear bodies trigger conflicting cell cycle signal-mediated cytotoxicity in leukemia cells |
| title_fullStr | Enlarged PML-nuclear bodies trigger conflicting cell cycle signal-mediated cytotoxicity in leukemia cells |
| title_full_unstemmed | Enlarged PML-nuclear bodies trigger conflicting cell cycle signal-mediated cytotoxicity in leukemia cells |
| title_short | Enlarged PML-nuclear bodies trigger conflicting cell cycle signal-mediated cytotoxicity in leukemia cells |
| title_sort | enlarged pml nuclear bodies trigger conflicting cell cycle signal mediated cytotoxicity in leukemia cells |
| url | https://doi.org/10.1038/s41419-025-07911-7 |
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