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<p>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 <i>JAK/STAT</i> mutations (predominantly in <i>JAK3</i> and <i>STAT5B</i>) 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 <i>JAK/STAT</i> mutations did not predict responses to pharmacologic STAT3/STAT5 degradation, elevated expression of <i>TOX, PAK6</i>, and <i>SPINT1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月15日

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

摘要

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.