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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."}]}],"bf:provisionActivity":[{"@type":"bf:Publication","bf:agent":[{"@type":"schema:Organization","schema:name":[{"@value":"Nature Publishing Group"}]}]}],"dce:rights":[{"@language":"eng","@value":"Copyright © 2025, The Author(s)"}],"dce:subject":[{"@type":"skos:Concept","skos:prefLabel":[{"@language":"eng","@value":"Leukaemia"}]},{"@type":"skos:Concept","skos:prefLabel":[{"@language":"eng","@value":"Targeted Therapies"}]},{"@type":"skos:Concept","skos:prefLabel":[{"@language":"eng","@value":"Translational Research"}]}],"dce:title":[{"@type":"bf:Title","bf:mainTitle":[{"@language":"eng","@value":"Dual STAT3\/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic 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