https://phaidra.vetmeduni.ac.at/o:4646 Dual STAT3/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic leukemia Dechow, Annika Annika Dechow Timonen, Sanna Sanna Timonen Ianevski, Aleksandr Aleksandr Ianevski Jiang, Qu Qu Jiang Wahnschaffe, Linus Linus Wahnschaffe Peng, Yayi Yayi Peng Jungherz, Dennis Dennis Jungherz Becker, Kerstin Kerstin Becker Neubauer, Heidi Heidi Neubauer 0000-0001-7372-7786 University of Veterinary Medicine Vienna Schoenefeldt, Susann Susann Schoenefeldt University of Veterinary Medicine Vienna de Araujo, Elvin D. Elvin D. de Araujo Gunning, P. P. Gunning Fleck, Roman Roman Fleck Schrader, Alexandra Alexandra Schrader Hallek, Michael Michael Hallek Pflug, Natali Natali Pflug Moriggl, Richard Richard Moriggl Aittokallio, Tero Tero Aittokallio Mustjoki, Satu Satu Mustjoki Braun, Till Till Braun Herling, Marco Marco Herling Nature Publishing Group journal article open access eng 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. Leukaemia Targeted Therapies Translational Research http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:4646/download 10.1038/s41375-025-02577-8 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Leukemia issn:1476-5551 VoR Leukemia 39 6 3.43 MB 2025