RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia

  • Nat Commun. 2025 Jan 16;16(1):492. doi: 10.1038/s41467-024-55643-7.
Tim Kong  1 ,  Angelo B A Laranjeira  1 ,  Christopher T Letson  1 ,  LaYow Yu  1 ,  Shuyang Lin  1 ,  Jared S Fowles  1 ,  Daniel A C Fisher  1 ,  Sherwin Ng  2 ,  Wei Yang  3 ,  Fan He  1 ,  Minyoung Youn  4 ,  Kailen Mark  4 ,  Ana San Jose  4 ,  Jingxian Liu  5  6 ,  Alexander B Kim  7  8 ,  Maggie J Cox  1 ,  Mary C Fulbright  1 ,  Aarthi Jayanthan  9 ,  Gerrit Los  9 ,  Stacey L Rentschler  2  10  11  12 ,  Li Ding  3  5  6  13 ,  Kathleen M Sakamoto  4 ,  Sandra E Dunn  9 ,  Grant A Challen  5 ,  Stephen T Oh  14  15  16
Affiliations
  • 1. Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 2. Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 3. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
  • 4. Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA.
  • 5. Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 6. McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA.
  • 7. Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
  • 8. Bursky Center for Human Immunology & Immunotherapy, Washington University School of Medicine, St. Louis, MO, USA.
  • 9. Phoenix Molecular Designs, Vancouver, BC, Canada, San Diego, CA, USA.
  • 10. Center for Noninvasive Cardiac Radioablation, Washington University School of Medicine, St. Louis, MO, USA.
  • 11. Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, USA.
  • 12. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
  • 13. Siteman Cancer Center, Washington University in St Louis, St Louis, MO, USA.
  • 14. Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 15. Bursky Center for Human Immunology & Immunotherapy, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 16. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
PMID: 39820365 DOI: 10.1038/s41467-024-55643-7
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.

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