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

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 and Stephen T. Oh ()
Additional contact information
Tim Kong: Washington University School of Medicine
Angelo B. A. Laranjeira: Washington University School of Medicine
Christopher T. Letson: Washington University School of Medicine
LaYow Yu: Washington University School of Medicine
Shuyang Lin: Washington University School of Medicine
Jared S. Fowles: Washington University School of Medicine
Daniel A. C. Fisher: Washington University School of Medicine
Sherwin Ng: Washington University School of Medicine
Wei Yang: Washington University School of Medicine
Fan He: Washington University School of Medicine
Minyoung Youn: Stanford University
Kailen Mark: Stanford University
Ana San Jose: Stanford University
Jingxian Liu: Washington University School of Medicine
Alexander B. Kim: Washington University School of Medicine
Maggie J. Cox: Washington University School of Medicine
Mary C. Fulbright: Washington University School of Medicine
Aarthi Jayanthan: Canada
Gerrit Los: Canada
Stacey L. Rentschler: Washington University School of Medicine
Li Ding: Washington University School of Medicine
Kathleen M. Sakamoto: Stanford University
Sandra E. Dunn: Canada
Grant A. Challen: Washington University School of Medicine
Stephen T. Oh: Washington University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55643-7

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