Dual STAT3/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic leukemia

Annika Dechow; Sanna Timonen; Aleksandr Ianevski; Qu Jiang; Linus Wahnschaffe; Yayi Peng; Dennis Jungherz; Kerstin Becker; Heidi Neubauer; Susann Schoenefeldt; Elvin D. de Araujo; P. Gunning; Roman Fleck; Alexandra Schrader; Michael Hallek; Natali Pflug; Richard Moriggl; Tero Aittokallio; Satu Mustjoki; Till Braun; Marco Herling

doi:10.1038/s41375-025-02577-8

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Title (eng)

Dual STAT3/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic leukemia

Author

Annika Dechow

Sanna Timonen

Aleksandr Ianevski

Qu Jiang

Linus Wahnschaffe

Yayi Peng

Dennis Jungherz

Kerstin Becker

Heidi Neubauer

University of Veterinary Medicine Vienna

Susann Schoenefeldt

University of Veterinary Medicine Vienna

Elvin D. de Araujo

P. Gunning

Roman Fleck

Alexandra Schrader

Michael Hallek

Natali Pflug

Richard Moriggl

Tero Aittokallio

Satu Mustjoki

Till Braun

Marco Herling

Abstract (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.

Keywords (eng)

LeukaemiaTargeted TherapiesTranslational Research

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4646

DOI

10.1038/s41375-025-02577-8

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Title (eng)