Abstract
The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation. JPX-0700/−0750 decreased the mRNA and protein levels of STAT3/5 targets involved in cancer survival, metabolism, and cell cycle progression, exhibiting nanomolar to low micromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases, activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative, or epigenetic-modifying STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. Both JPX-0700/−0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | e70001 |
| Tidsskrift | HemaSphere |
| Vol/bind | 8 |
| Udgave nummer | 12 |
| Antal sider | 15 |
| ISSN | 2572-9241 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:Austrian Science Fund grant (FWF) SFB F04707-B20 (HS, RM). Austrian Science Fund grant (FWF) SFB-F06105 (RM, CW, HAN). Austrian Science Fund grant (FWF) P34781 (LK). The Christian-Doppler Lab for Applied Metabolomics (CDL-AM) in cooperation with Siemens Medical Solutions USA, Inc. (DP, LK). The European Union supported the Transcan-II initiative ERANET-PLL (MH, DP, RM). The European Union supported ERA PerMed JAKSTAT-TARGET (SM, MH, PTG, TA, HAN). The European Union Horizon 2020 Marie Sklodowska-Curie Innovative Training Network: \u201CFANTOM\u201D n. 101072735, \u201CeRaDicate\u201D, n. 101119427 (LK). The Vienna Science and Technology Fund (WWTF) LS19-018 (LK). The authors wish to thank Safia Zahma, Emi Miyakoda, and Michael Machtinger from the Institute of Animal Breeding and Genetics at the University of Veterinary Medicine Vienna for technical support in histology and during in vivo experiments, and Stefan Stoiber from the Medical University of Vienna for technical support during in vivo experiments and for his support while designing figures. This research was supported using resources of the VetCore Facility (VetImaging | VetBiobank) of the University of Veterinary Medicine Vienna.
Funding Information:
Austrian Science Fund grant (FWF) SFB F04707\u2010B20 (HS, RM). Austrian Science Fund grant (FWF) SFB\u2010F06105 (RM, CW, HAN). Austrian Science Fund grant (FWF) P34781 (LK). The Christian\u2010Doppler Lab for Applied Metabolomics (CDL\u2010AM) in cooperation with Siemens Medical Solutions USA, Inc. (DP, LK). The European Union supported the Transcan\u2010II initiative ERANET\u2010PLL (MH, DP, RM). The European Union supported ERA PerMed JAKSTAT\u2010TARGET (SM, MH, PTG, TA, HAN). The European Union Horizon 2020 Marie Sklodowska\u2010Curie Innovative Training Network: \u201CFANTOM\u201D n. 101072735, \u201CeRaDicate\u201D, n. 101119427 (LK). The Vienna Science and Technology Fund (WWTF) LS19\u2010018 (LK).
Publisher Copyright:
© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.