Annika Dechow Annika Dechow Sanna Timonen Sanna Timonen Aleksandr Ianevski Aleksandr Ianevski Qu Jiang Qu Jiang Linus Wahnschaffe Linus Wahnschaffe Yayi Peng Yayi Peng Dennis Jungherz Dennis Jungherz Kerstin Becker Kerstin Becker Heidi Neubauer Heidi Neubauer Susann Schoenefeldt Susann Schoenefeldt Elvin D. de Araujo Elvin D. de Araujo P. Gunning P. Gunning Roman Fleck Roman Fleck Alexandra Schrader Alexandra Schrader Michael Hallek Michael Hallek Natali Pflug Natali Pflug Richard Moriggl Richard Moriggl Tero Aittokallio Tero Aittokallio Satu Mustjoki Satu Mustjoki Till Braun Till Braun Marco Herling Marco Herling Nature Publishing Group 2025 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. PDFDocument eng 2025-12-01T09:51:46.262711Z 2025 Leukaemia Targeted Therapies Translational Research 3591720 b application/pdf http://creativecommons.org/licenses/by/4.0/