PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expression
Abstract Our study explores the complex dynamics of the integrated stress response (ISR) axis, highlighting PIM2 kinase’s critical role and its interaction with the BCL2 protein family, uncovering key mechanisms of cell survival and tumor progression. Elevated PIM2 expression, a marker of various ca...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55572-5 |
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| _version_ | 1841559272119336960 |
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| author | Marion Haas Sabrina Cherfa Léa Nguyen Maxence Bourgoin Gersende Caron Elise Dessauge Tony Marchand Laurent Delpy Patrick Auberger Jérôme Moreaux Arnaud Jacquel Thierry Fest |
| author_facet | Marion Haas Sabrina Cherfa Léa Nguyen Maxence Bourgoin Gersende Caron Elise Dessauge Tony Marchand Laurent Delpy Patrick Auberger Jérôme Moreaux Arnaud Jacquel Thierry Fest |
| author_sort | Marion Haas |
| collection | DOAJ |
| description | Abstract Our study explores the complex dynamics of the integrated stress response (ISR) axis, highlighting PIM2 kinase’s critical role and its interaction with the BCL2 protein family, uncovering key mechanisms of cell survival and tumor progression. Elevated PIM2 expression, a marker of various cancers, often correlates with disease aggressiveness. Using a model of normal and malignant plasma cells, we show that inhibiting PIM2 kinase inhibits phosphorylated BAD production and activates ISR-mediated NOXA expression. This shift towards MCL1 dependence underscores the synergy achieved through combined PIM/MCL1 inhibition, driven largely by ISR-mediated NOXA expression. In mouse xenograft models, dual targeting of PIM2 and MCL1 effectively controls tumor growth—a response reversed by ISR-specific inhibition and upregulation of genes linked to tumor cell dissemination. This work elucidates the molecular intricacies of PIM2 inhibition and its implications for cancer therapy, especially in tumors with elevated PIM2 expression. |
| format | Article |
| id | doaj-art-33d5135d0b5e45fe979dee3641915203 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-33d5135d0b5e45fe979dee36419152032025-01-05T12:37:10ZengNature PortfolioNature Communications2041-17232025-01-0116112010.1038/s41467-024-55572-5PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expressionMarion Haas0Sabrina Cherfa1Léa Nguyen2Maxence Bourgoin3Gersende Caron4Elise Dessauge5Tony Marchand6Laurent Delpy7Patrick Auberger8Jérôme Moreaux9Arnaud Jacquel10Thierry Fest11Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236Université Côte d’Azur, INSERM U1065, C3MUniversité de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236Université de Limoges, UMR CNRS 7276, INSERM U1262Université Côte d’Azur, INSERM U1065, C3MInstitut de Génétique Humaine, UMR 9002 CNRS-UM; Pôle de biologie, Centre Hospitalier UniversitaireUniversité Côte d’Azur, INSERM U1065, C3MUniversité de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236Abstract Our study explores the complex dynamics of the integrated stress response (ISR) axis, highlighting PIM2 kinase’s critical role and its interaction with the BCL2 protein family, uncovering key mechanisms of cell survival and tumor progression. Elevated PIM2 expression, a marker of various cancers, often correlates with disease aggressiveness. Using a model of normal and malignant plasma cells, we show that inhibiting PIM2 kinase inhibits phosphorylated BAD production and activates ISR-mediated NOXA expression. This shift towards MCL1 dependence underscores the synergy achieved through combined PIM/MCL1 inhibition, driven largely by ISR-mediated NOXA expression. In mouse xenograft models, dual targeting of PIM2 and MCL1 effectively controls tumor growth—a response reversed by ISR-specific inhibition and upregulation of genes linked to tumor cell dissemination. This work elucidates the molecular intricacies of PIM2 inhibition and its implications for cancer therapy, especially in tumors with elevated PIM2 expression.https://doi.org/10.1038/s41467-024-55572-5 |
| spellingShingle | Marion Haas Sabrina Cherfa Léa Nguyen Maxence Bourgoin Gersende Caron Elise Dessauge Tony Marchand Laurent Delpy Patrick Auberger Jérôme Moreaux Arnaud Jacquel Thierry Fest PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expression Nature Communications |
| title | PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expression |
| title_full | PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expression |
| title_fullStr | PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expression |
| title_full_unstemmed | PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expression |
| title_short | PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expression |
| title_sort | pim2 inhibition promotes mcl1 dependency in plasma cells involving integrated stress response driven noxa expression |
| url | https://doi.org/10.1038/s41467-024-55572-5 |
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