phaidra.vetmeduni.ac.at o:4646 DOI 10.1038/s41375-025-02577-8 Dual STAT3/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic leukemia 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. eng Leukaemia Targeted Therapies Translational Research 2025-12-01T09:51:46.463Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Dechow;Annika; FN:Annika Dechow END:VCARD BEGIN:VCARD VERSION:3.0 N:Timonen;Sanna; FN:Sanna Timonen END:VCARD BEGIN:VCARD VERSION:3.0 N:Ianevski;Aleksandr; FN:Aleksandr Ianevski END:VCARD BEGIN:VCARD VERSION:3.0 N:Jiang;Qu; FN:Qu Jiang END:VCARD BEGIN:VCARD VERSION:3.0 N:Wahnschaffe;Linus; FN:Linus Wahnschaffe END:VCARD BEGIN:VCARD VERSION:3.0 N:Peng;Yayi; FN:Yayi Peng END:VCARD BEGIN:VCARD VERSION:3.0 N:Jungherz;Dennis; FN:Dennis Jungherz END:VCARD BEGIN:VCARD VERSION:3.0 N:Becker;Kerstin; FN:Kerstin Becker END:VCARD BEGIN:VCARD VERSION:3.0 N:Neubauer;Heidi; FN:Heidi Neubauer X-ORCID:https://orcid.org/0000-0001-7372-7786 END:VCARD BEGIN:VCARD VERSION:3.0 N:Schoenefeldt;Susann; FN:Susann Schoenefeldt END:VCARD BEGIN:VCARD VERSION:3.0 N:de Araujo;Elvin D.; FN:Elvin D. de Araujo END:VCARD BEGIN:VCARD VERSION:3.0 N:Gunning;P.; FN:P. Gunning END:VCARD BEGIN:VCARD VERSION:3.0 N:Fleck;Roman; FN:Roman Fleck END:VCARD BEGIN:VCARD VERSION:3.0 N:Schrader;Alexandra; FN:Alexandra Schrader END:VCARD BEGIN:VCARD VERSION:3.0 N:Hallek;Michael; FN:Michael Hallek END:VCARD BEGIN:VCARD VERSION:3.0 N:Pflug;Natali; FN:Natali Pflug END:VCARD BEGIN:VCARD VERSION:3.0 N:Moriggl;Richard; FN:Richard Moriggl END:VCARD BEGIN:VCARD VERSION:3.0 N:Aittokallio;Tero; FN:Tero Aittokallio END:VCARD BEGIN:VCARD VERSION:3.0 N:Mustjoki;Satu; FN:Satu Mustjoki END:VCARD BEGIN:VCARD VERSION:3.0 N:Braun;Till; FN:Till Braun END:VCARD BEGIN:VCARD VERSION:3.0 N:Herling;Marco; FN:Marco Herling END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 3591720 https://phaidra.vetmeduni.ac.at/o:4646 https://phaidra.vetmeduni.ac.at/api/object/o:4646/thumbnail LOMv1.0 discipline