A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia
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. Pictorial representation depicting upregulation of STAT3 and MCL1 in venetoclax resistant myeloid malignancies such as MDS and AML causing mitochondrial structural abnormalities and dysfunction. By using specific STAT3 degrader, STAT3 inhibition, and thereby indirect downregulation of MCL1 can be a promising therapeutic intervention to target drug resistant clones in MDS and AML.
Authors
- H. Zhang
- Anna Skwarska (ORCID: https://orcid.org/0000-0002-0979-026X)
- Eduardo Sabino de Camargo Magalhães (ORCID: https://orcid.org/0000-0002-7726-4827)
- Abdullah Khasawneh (ORCID: https://orcid.org/0000-0002-8324-4048)
- Ioannis Mantzaris (ORCID: https://orcid.org/0000-0001-8346-5767)
- Jared Gollob (ORCID: https://orcid.org/0009-0008-0281-715X)
- Keisuke Ito (ORCID: https://orcid.org/0000-0002-6702-9735)
- Shanisha Gordon-Mitchell (ORCID: https://orcid.org/0009-0007-5335-0046)
- Kira Gritsman (ORCID: https://orcid.org/0000-0002-1367-1167)
- S. Colla
- Kimberly Zaldaña (ORCID: https://orcid.org/0009-0002-0300-5176)
- Nadege Gitego (ORCID: https://orcid.org/0009-0004-1306-5505)
- Mendel Goldfinger (ORCID: https://orcid.org/0000-0002-4347-173X)
- Sergei B. Koralov (ORCID: https://orcid.org/0000-0002-4843-3791)
- Stefan Hübner (ORCID: https://orcid.org/0000-0001-7546-4393)
- Joyoti Dey
- Aditi Shastri
- Yi Hua Qiu (ORCID: https://orcid.org/0009-0007-5554-5998)
- Samarpana Chakraborty (ORCID: https://orcid.org/0009-0005-1273-7960)
- S M Kornblau
- B. W. Brown
- Kith Pradhan
- Feiyang Ma
- Srinivas Aluri
- Yang Shi
- Claudia Morganti
- Eric Feldman
- Evripidis Gavathiotis
- Divij Verma
- Amit Verma
- Bianca Rivera Pena
- Yoko Tabe
- Marina Konopleva
Institutions
- Northwestern University (US)
- Albert Einstein College of Medicine (US)
- University Medical Center Groningen (NL)
- Montefiore Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of Groningen (NL)
- Juntendo University (JP)
- NYU Langone Health (US)
Publication Details
- Journal
- Leukemia
- Published
- 2026-02-17
- DOI
- https://doi.org/10.1038/s41375-026-02883-9
- Citations
- 1
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 35.41
Funders
- Albert Einstein College of Medicine, Yeshiva University