http://creativecommons.org/licenses/by/4.0/ Leukaemia Targeted Therapies Translational Research T-prolymphocytic leukemia (T-PLL) is a rare, aggressive T-cell malignancy with poor outcomes and an urgent need for new therapeutic approaches. Integrating genomic data and new transcriptomic profiling, we identified recurrent JAK/STAT mutations (predominantly in JAK3 and STAT5B) as hallmarks in a cohort of 335 T-PLL cases. In line, transcriptomic and protein analyses revealed constitutive JAK/STAT activation in virtually all samples. Consequently, we explored the anti-leukemic potential of dual STAT3/STAT5 non-PROTAC degraders in T-PLL, with JPX-1244 as our lead substance. JPX-1244 efficiently and selectively induced cell death in primary T-PLL samples, including those resistant to conventional therapies, by blocking STAT3 and STAT5 phosphorylation and by inducing their degradation. The extent of STAT3/STAT5 degradation directly correlated with cytotoxicity. RNA-sequencing confirmed the treatment-related downregulation of STAT5 target genes. While JAK/STAT mutations did not predict responses to pharmacologic STAT3/STAT5 degradation, elevated expression of TOX, PAK6, and SPINT1 were associated with drug sensitivity. In subsequent combination screenings, cladribine, venetoclax, and azacytidine emerged as most effective combination partners of STAT3/STAT5 degraders, even in low-responding T-PLL samples, all synergistically reducing STAT5 phosphorylation. These findings highlight dual STAT3/STAT5 inhibition, particularly in combination with hypomethylating and BCL2-targeting agents, as a promising interventional approach in T-PLL, warranting further investigation. Text Wissenschaftlicher Artikel application/pdf Leukemia Dual STAT3/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic leukemia 2025 Nature Publishing Group Copyright © 2025, The Author(s) open access Testo Articolo di rivista eng Annika Dechow Sanna Timonen Aleksandr Ianevski Qu Jiang Linus Wahnschaffe Yayi Peng Dennis Jungherz Kerstin Becker Heidi Neubauer Susann Schoenefeldt Elvin D. de Araujo P. Gunning Roman Fleck Alexandra Schrader Michael Hallek Natali Pflug Richard Moriggl Tero Aittokallio Satu Mustjoki Till Braun Marco Herling doi:10.1038/s41375-025-02577-8 Text journal article https://phaidra.vetmeduni.ac.at/o:4646