RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia
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.
Authors
- Stephen T. Oh (ORCID: https://orcid.org/0000-0002-8564-5400)
- Shuyang Lin (ORCID: https://orcid.org/0000-0002-9522-7798)
- Sherwin Ng
- Tim Kong
- Jared S. Fowles (ORCID: https://orcid.org/0000-0002-7614-5447)
- Maggie J. Cox
- Aarthi Jayanthan
- Christopher T. Letson (ORCID: https://orcid.org/0000-0002-1780-2638)
- Wei Yang (ORCID: https://orcid.org/0000-0002-6275-5981)
- Angelo B. A. Laranjeira (ORCID: https://orcid.org/0000-0002-6772-0956)
- Kathleen M. Sakamoto (ORCID: https://orcid.org/0000-0003-0494-8838)
- LaYow Yu (ORCID: https://orcid.org/0009-0004-7849-0844)
- Stacey Rentschler (ORCID: https://orcid.org/0000-0002-1744-1238)
- Mary C. Fulbright
- Grant Anthony Challen (ORCID: https://orcid.org/0000-0003-4669-8814)
- Kailen Mark (ORCID: https://orcid.org/0009-0004-6990-5761)
- Sandra E. Dunn
- Fan He (ORCID: https://orcid.org/0000-0001-8598-4472)
- Alexander B. Kim (ORCID: https://orcid.org/0000-0002-6425-4566)
- Gerrit Los
- M. Youn (ORCID: https://orcid.org/0000-0002-8112-2346)
- Li Ding (ORCID: https://orcid.org/0000-0003-1517-2975)
- Jingxian Liu
- Daniel A.C. Fisher
Institutions
- James S. McDonnell Foundation (US)
- Washington University in St. Louis (US)
- Quantum Design (United States) (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-16
- DOI
- https://doi.org/10.1038/s41467-024-55643-7
- Citations
- 10
- Primary Topic
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 16.25
Funders
- U.S. Department of Defense
- Leukemia and Lymphoma Society
- Memorial Sloan-Kettering Cancer Center
- MPN Research Foundation
- Institute of Clinical and Translational Sciences
- McGill University
- Edward P. Evans Foundation
- Alvin J. Siteman Cancer Center
- National Institutes of Health
- Canadian Institutes of Health Research
- National Cancer Institute
- National Center for Advancing Translational Sciences
- Hyundai Hope On Wheels