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Integrating genomic data and new transcriptomic profiling, we identified recurrent <jats:italic>JAK\/STAT<\/jats:italic> mutations (predominantly in <jats:italic>JAK3<\/jats:italic> and <jats:italic>STAT5B<\/jats:italic>) 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 <jats:italic>JAK\/STAT<\/jats:italic> mutations did not predict responses to pharmacologic STAT3\/STAT5 degradation, elevated expression of <jats:italic>TOX, PAK6<\/jats:italic>, and <jats:italic>SPINT1<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41375-025-02577-8","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T11:49:07Z","timestamp":1744717747000},"page":"1435-1448","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dual STAT3\/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic leukemia"],"prefix":"10.1038","volume":"39","author":[{"given":"Annika","family":"Dechow","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8139-5950","authenticated-orcid":false,"given":"Sanna","family":"Timonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandr","family":"Ianevski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8517-7750","authenticated-orcid":false,"given":"Qu","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linus","family":"Wahnschaffe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayi","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Jungherz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7897-7181","authenticated-orcid":false,"given":"Kerstin","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7372-7786","authenticated-orcid":false,"given":"Heidi A.","family":"Neubauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susann","family":"Sch\u00f6nefeldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0716-2830","authenticated-orcid":false,"given":"Elvin","family":"de Araujo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Gunning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Fleck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Schrader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7425-4455","authenticated-orcid":false,"given":"Michael","family":"Hallek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natali","family":"Pflug","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0918-9463","authenticated-orcid":false,"given":"Richard","family":"Moriggl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0886-9769","authenticated-orcid":false,"given":"Tero","family":"Aittokallio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0816-8241","authenticated-orcid":false,"given":"Satu","family":"Mustjoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0854-7815","authenticated-orcid":false,"given":"Till","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Herling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"2577_CR1","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1182\/blood.2019000402","volume":"134","author":"PB Staber","year":"2019","unstructured":"Staber PB, Herling M, Bellido M, Jacobsen ED, Davids MS, Kadia TM, et al. 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