2. Academic Validation
  3. RSK1 dependency in FLT3-ITD acute myeloid leukemia

RSK1 dependency in FLT3-ITD acute myeloid leukemia

  • Blood Cancer J. 2024 Nov 26;14(1):207. doi: 10.1038/s41408-024-01187-4.
Tim Kong 1,  Angelo B A Laranjeira 1,  Christopher T Letson 1,  LaYow Yu 1,  Fan He 1,  Aarthi Jayanthan 2 3,  Gerrit Los 2 3,  Sandra E Dunn 2 3,  Grant A Challen 4,  Stephen T Oh 5 6 7
Affiliations

Affiliations

  • 1 Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 2 Phoenix Molecular Designs, Vancouver, BC, Canada.
  • 3 Phoenix Molecular Designs, San Diego, CA, USA.
  • 4 Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 5 Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. stoh@wustl.edu.
  • 6 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. stoh@wustl.edu.
  • 7 Immunomonitoring Laboratory, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA. stoh@wustl.edu.
PMID: 39592591 DOI: 10.1038/s41408-024-01187-4
Abstract

Internal tandem duplications (ITD) in fms-like tyrosine kinase 3 (FLT3) represent the most common genetic alteration in de novo acute myeloid leukemia (AML). Here, we identify ribosomal protein s6 kinase a1 (RSK1) as a core dependency in FLT3-ITD AML and unveil the existence of crucial bi-directional regulation. RSK1 perturbation resulted in marked Apoptosis and abrogated phosphorylation of FLT3 and associated downstream signaling cascades in FLT3-ITD AML cell lines. Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Importantly, multivariate analysis revealed heightened expression of RPS6KA1 and USP1 to be associated with poor patient prognosis, and these effectors may serve as biomarkers predictive of patient survival and therapeutic response to FLT3-ITD inhibitors. Lastly, RSK1 inhibition utilizing a first-in-class RSK inhibitor, PMD-026, that is currently undergoing Phase 2 development for breast Cancer, diminished leukemic disease burden in MV4-11 xenograft and syngeneic FLT3ITDTET2KO leukemia models. These findings illustrate an unconventional and promising therapeutic strategy targeting FLT3-ITD leukemia.

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