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.

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Publication Details

Journal
Leukemia
Published
2025-04-15
DOI
https://doi.org/10.1038/s41375-025-02577-8
Citations
3
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
4.88

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article

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

Qu Jiang, Elvin D. de Araujo, Heidi A. Neubauer, Satu M. Mustjoki et al.
3 citations
Leukemia
Chronic Lymphocytic Leukemia Research
4.88
article

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

Qu Jiang, Elvin D. de Araujo, Heidi A. Neubauer, Satu M. Mustjoki, Richard Moriggl, Tero A. Aittokallio, Dennis Jungherz, Alexandra Schrader, Sanna Timonen, Marco Herling, Susann Schönefeldt, Kerstin Becker, Patrick T. Gunning, Linus Wahnschaffe, Annika Dechow, Aleksandr Ianevski, Yayi Peng, Roman Fleck, Natali Pflug, Michael J. Hallek, Till Braun
article en
3 citations

Abstract

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.

LeukemiaVol. 39(6)
Université Claude Bernard Lyon 1 (FR), École Normale Supérieure de Lyon (FR), Oslo University Hospital (NO), Centre National de la Recherche Scientifique (FR), University of Helsinki (FI), University of Veterinary Medicine Vienna (AT), Inserm (FR), Lyon College (US), University of Cologne (DE), University of Salzburg (AT), Helsinki University Hospital (FI), Düsseldorf University Hospital (DE), Integrated Oncology (United States) (US), Moixa (United Kingdom) (GB), University Hospital Leipzig (DE), Institute for Molecular Medicine Finland (FI), ADD Centre (CA), University Hospital Cologne (DE), Centre International de Recherche en Infectiologie (FR), Heinrich Heine University Düsseldorf (DE)
European Commission, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Signe ja Ane Gyllenbergin Säätiö, Fondation de France, José Carreras Leukämie-Stiftung, Deutsche Krebshilfe, Sächsisches Staatsministerium für Wissenschaft und Kunst, Sigrid Juséliuksen Säätiö, Institut National Du Cancer, Syöpäjärjestöt, Helsinki Institute of Life Science, Helsingin Yliopisto
Good health and well-being
Openalex Percentile: Top 6%
Chronic Lymphocytic Leukemia Research
4.88
DOIOpen Access PDFOpenAlex
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