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<p>Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with a poor prognosis. Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader.</p><p></p>

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A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月17日

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  • Samarpana Chakraborty,
  • Claudia Morganti,
  • Kimberly Zaldana,
  • Bianca Rivera Pena,
  • Hui Zhang,
  • Divij Verma,
  • Nadege Gitego,
  • Feiyang Ma,
  • Srinivas Aluri,
  • Kith Pradhan,
  • Shanisha Gordon-Mitchell,
  • Ioannis Mantzaris,
  • Mendel Goldfinger,
  • Eric Feldman,
  • Kira Gritsman,
  • Yang Shi,
  • Stefan Hubner,
  • Yi Hua Qiu,
  • Brandon D. Brown,
  • Abdullah Khasawneh,
  • Anna Skwarska,
  • Eduardo Sabino de Camargo Magalhães,
  • Amit Verma,
  • Marina Konopleva,
  • Yoko Tabe,
  • Evripidis Gavathiotis,
  • Simona Colla,
  • Jared Gollob,
  • Joyoti Dey,
  • Steven M. Kornblau,
  • Sergei B. Koralov,
  • Keisuke Ito,
  • Aditi Shastri

摘要

Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with a poor prognosis. Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader.