Daniel Pölöske Daniel Pölöske Helena Sorger Helena Sorger Anna Schönbichler Anna Schönbichler Elvin D. de Araujo Elvin D. de Araujo Heidi A Neubauer Heidi A Neubauer Anna Orlova Anna Orlova Sanna H. Timonen Sanna H. Timonen Diaaeldin I. Abdallah Diaaeldin I. Abdallah Aleksandr Ianevski Aleksandr Ianevski Heikki Kuusanmäki Heikki Kuusanmäki Marta Surbek Marta Surbek Elisabeth Heyes Elisabeth Heyes Thomas Eder Thomas Eder Christina Wagner Christina Wagner Tobias Suske Tobias Suske Martin L. Metzelder Martin L. Metzelder Michael Bergmann Michael Bergmann Maik Dahlhoff Maik Dahlhoff Florian Grebien Florian Grebien Roman Fleck Roman Fleck Christine Pirker Christine Pirker Walter Berger Walter Berger Emir Hadzijusufovic Emir Hadzijusufovic Wolfgang R. Sperr Wolfgang R. Sperr Lukas Kenner Lukas Kenner Peter Peter Peter Peter Tero Aittokallio Tero Aittokallio Marco Herling Marco Herling Satu Mustjoki Satu Mustjoki Patrick T. Gunning Patrick T. Gunning Richard Moriggl Richard Moriggl Wiley 2024 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. PDFDocument eng 2025-01-20T09:05:47.744912Z 2024 Survival Model Lines 4355691 b application/pdf application/pdf http://creativecommons.org/licenses/by-nc-nd/4.0/