RSK1 dependency in FLT3-ITD acute myeloid leukemia.

Autor: Kong T; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Laranjeira ABA; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Letson CT; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Yu L; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., He F; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Jayanthan A; Phoenix Molecular Designs, Vancouver, BC, Canada.; Phoenix Molecular Designs, San Diego, CA, USA., Los G; Phoenix Molecular Designs, Vancouver, BC, Canada.; Phoenix Molecular Designs, San Diego, CA, USA., Dunn SE; Phoenix Molecular Designs, Vancouver, BC, Canada.; Phoenix Molecular Designs, San Diego, CA, USA., Challen GA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Oh ST; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. stoh@wustl.edu.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. stoh@wustl.edu.; Immunomonitoring Laboratory, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA. stoh@wustl.edu.
Jazyk: angličtina
Zdroj: Blood cancer journal [Blood Cancer J] 2024 Nov 26; Vol. 14 (1), pp. 207. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1038/s41408-024-01187-4
Abstrakt: 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 Flt3 ITD Tet2 KO leukemia models. These findings illustrate an unconventional and promising therapeutic strategy targeting FLT3-ITD leukemia.
Competing Interests: Competing interests: STO has served as a consultant for Kartos Therapeutics, CTI BioPharma, Celgene/Bristol Myers Squibb, Disc Medicine, Protagonist, Blueprint Medicines, Cogent, PharmaEssentia, Constellation, Geron, Abbvie, Sierra Oncology, and Incyte. MH, GL, and SED, are employees of Phoenix Molecular Designs. GAC has received funding for consulting and/or sponsored research from Incyte, Ajax Therapeutics, and Renagade Therapeutics. All other authors disclose no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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