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TRIB3 Stabilizes High TWIST1 Expression to Promote Rapid APL Progression and ATRA Resistance
Jian Lin1, Wu Zhang2, Li-Ting Niu1
1State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao-Tong University, Shanghai, China.
Summary
This study reveals TWIST1 is crucial for acute promyelocytic leukemia (APL) survival and ATRA resistance. Disrupting the TWIST1-TRIB3 interaction with a novel peptide reverses resistance and improves outcomes for APL patients.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Acute promyelocytic leukemia (APL) patients often face resistance to differentiation therapy and fatal bleeding.
- Understanding resistance mechanisms is crucial for developing effective treatments to prevent early mortality.
Purpose of the Study:
- To investigate the molecular mechanisms underlying all-trans retinoic acid (ATRA) resistance in APL.
- To identify novel therapeutic strategies to overcome ATRA resistance and reduce early death in APL patients.
Main Methods:
- Gain- and loss-of-function assays to determine TWIST1's role in APL.
- In vivo and in vitro experiments to study the TWIST1-TRIB3 interaction.
- Functional screening of synthetic peptides targeting the TWIST1 WR domain.
Main Results:
- TWIST1, an EMT-inducing transcription factor, is highly expressed and critical for leukemic cell survival in APL.
- TRIB3 stabilizes TWIST1 by inhibiting its ubiquitination; their coexpression is high in APL.
- Disrupting the TRIB3/TWIST1 interaction via a novel peptide reverses ATRA resistance and improves sensitivity.
Conclusions:
- TWIST1 plays an essential role in APL pathogenesis as an EMT-TF.
- Targeting the TRIB3/TWIST1 interaction offers a promising therapeutic strategy to reverse induction therapy resistance and prevent early death in APL.
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