RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia
Abstract Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferati...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55643-7 |
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| author | Tim Kong Angelo B. A. Laranjeira Christopher T. Letson LaYow Yu Shuyang Lin Jared S. Fowles Daniel A. C. Fisher Sherwin Ng Wei Yang Fan He Minyoung Youn Kailen Mark Ana San Jose Jingxian Liu Alexander B. Kim Maggie J. Cox Mary C. Fulbright Aarthi Jayanthan Gerrit Los Stacey L. Rentschler Li Ding Kathleen M. Sakamoto Sandra E. Dunn Grant A. Challen Stephen T. Oh |
| author_facet | Tim Kong Angelo B. A. Laranjeira Christopher T. Letson LaYow Yu Shuyang Lin Jared S. Fowles Daniel A. C. Fisher Sherwin Ng Wei Yang Fan He Minyoung Youn Kailen Mark Ana San Jose Jingxian Liu Alexander B. Kim Maggie J. Cox Mary C. Fulbright Aarthi Jayanthan Gerrit Los Stacey L. Rentschler Li Ding Kathleen M. Sakamoto Sandra E. Dunn Grant A. Challen Stephen T. Oh |
| author_sort | Tim Kong |
| collection | DOAJ |
| description | Abstract Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing of 158 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes. Supported by mass cytometry (CyTOF) profiling, we reveal aberrant networks of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation. Combining ATAC-Seq, CUT&Tag, RNA-seq, and CyTOF, we demonstrate that targeting of ribosomal protein S6 kinase A1 (RSK1) suppresses NFκB activation and diminishes pro-inflammatory mediators including tumor necrosis factor (TNF) associated with MPN disease severity and transformation. We further evaluate a therapeutic approach utilizing a first-in-class RSK inhibitor, PMD-026, currently in Phase 2 development for breast cancer, for use in myeloid malignancies. Treatment with PMD-026 suppressed disease burden across seven syngeneic and patient-derived xenograft leukemia mouse models spanning the spectrum of driver and disease-modifying mutations. These findings uncover a therapeutic avenue for a conserved dependency across MPN and sAML. |
| format | Article |
| id | doaj-art-d4326f5996964e6a98deb7e11d27e9d1 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d4326f5996964e6a98deb7e11d27e9d12025-01-19T12:31:35ZengNature PortfolioNature Communications2041-17232025-01-0116112010.1038/s41467-024-55643-7RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemiaTim Kong0Angelo B. A. Laranjeira1Christopher T. Letson2LaYow Yu3Shuyang Lin4Jared S. Fowles5Daniel A. C. Fisher6Sherwin Ng7Wei Yang8Fan He9Minyoung Youn10Kailen Mark11Ana San Jose12Jingxian Liu13Alexander B. Kim14Maggie J. Cox15Mary C. Fulbright16Aarthi Jayanthan17Gerrit Los18Stacey L. Rentschler19Li Ding20Kathleen M. Sakamoto21Sandra E. Dunn22Grant A. Challen23Stephen T. Oh24Division of Hematology, Department of Medicine, Washington University School of MedicineDivision of Hematology, Department of Medicine, Washington University School of MedicineDivision of Hematology, Department of Medicine, Washington University School of MedicineDivision of Hematology, Department of Medicine, Washington University School of MedicineDivision of Hematology, Department of Medicine, Washington University School of MedicineDivision of Hematology, Department of Medicine, Washington University School of MedicineDivision of Hematology, Department of Medicine, Washington University School of MedicineCardiovascular Division, Department of Medicine, Washington University School of MedicineDepartment of Genetics, Washington University School of MedicineDivision of Hematology, Department of Medicine, Washington University School of MedicineDivision of Hematology/Oncology, Department of Pediatrics, Stanford UniversityDivision of Hematology/Oncology, Department of Pediatrics, Stanford UniversityDivision of Hematology/Oncology, Department of Pediatrics, Stanford UniversityDivision of Oncology, Department of Medicine, Washington University School of MedicineDepartment of Radiation Oncology, Washington University School of MedicineDivision of Hematology, Department of Medicine, Washington University School of MedicineDivision of Hematology, Department of Medicine, Washington University School of MedicinePhoenix Molecular Designs, Vancouver, BC, CanadaPhoenix Molecular Designs, Vancouver, BC, CanadaCardiovascular Division, Department of Medicine, Washington University School of MedicineDepartment of Genetics, Washington University School of MedicineDivision of Hematology/Oncology, Department of Pediatrics, Stanford UniversityPhoenix Molecular Designs, Vancouver, BC, CanadaDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Hematology, Department of Medicine, Washington University School of MedicineAbstract Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing of 158 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes. Supported by mass cytometry (CyTOF) profiling, we reveal aberrant networks of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation. Combining ATAC-Seq, CUT&Tag, RNA-seq, and CyTOF, we demonstrate that targeting of ribosomal protein S6 kinase A1 (RSK1) suppresses NFκB activation and diminishes pro-inflammatory mediators including tumor necrosis factor (TNF) associated with MPN disease severity and transformation. We further evaluate a therapeutic approach utilizing a first-in-class RSK inhibitor, PMD-026, currently in Phase 2 development for breast cancer, for use in myeloid malignancies. Treatment with PMD-026 suppressed disease burden across seven syngeneic and patient-derived xenograft leukemia mouse models spanning the spectrum of driver and disease-modifying mutations. These findings uncover a therapeutic avenue for a conserved dependency across MPN and sAML.https://doi.org/10.1038/s41467-024-55643-7 |
| spellingShingle | Tim Kong Angelo B. A. Laranjeira Christopher T. Letson LaYow Yu Shuyang Lin Jared S. Fowles Daniel A. C. Fisher Sherwin Ng Wei Yang Fan He Minyoung Youn Kailen Mark Ana San Jose Jingxian Liu Alexander B. Kim Maggie J. Cox Mary C. Fulbright Aarthi Jayanthan Gerrit Los Stacey L. Rentschler Li Ding Kathleen M. Sakamoto Sandra E. Dunn Grant A. Challen Stephen T. Oh RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia Nature Communications |
| title | RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia |
| title_full | RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia |
| title_fullStr | RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia |
| title_full_unstemmed | RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia |
| title_short | RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia |
| title_sort | rsk1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia |
| url | https://doi.org/10.1038/s41467-024-55643-7 |
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