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. stoh@wustl.edu.
15 Bursky Center for Human Immunology & Immunotherapy, Washington University School of Medicine, St. Louis, MO, USA. stoh@wustl.edu.
16 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. stoh@wustl.edu.

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-10510

BI-D1870

99.72%, RSK Inhibitor

Ribosomal S6 Kinase (RSK); Autophagy

Cancer

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