TRIB3 Stabilizes High TWIST1 Expression to Promote Rapid APL Progression and ATRA Resistance

The resistance to differentiation therapy and early death caused by fatal bleeding endangers the health of a significant proportion of patients with acute promyelocytic leukemia (APL). This study aims to investigate the molecular mechanisms of all- retinoic acid (ATRA) resistance and uncover new pot...

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Published in:Clinical cancer research 2019-10, Vol.25 (20), p.6228-6242
Main Authors: Lin, Jian, Zhang, Wu, Niu, Li-Ting, Zhu, Yong-Mei, Weng, Xiang-Qin, Sheng, Yan, Zhu, Jiang, Xu, Jie
Format: Article
Language:English
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Summary:The resistance to differentiation therapy and early death caused by fatal bleeding endangers the health of a significant proportion of patients with acute promyelocytic leukemia (APL). This study aims to investigate the molecular mechanisms of all- retinoic acid (ATRA) resistance and uncover new potential therapeutic strategies to block the rapid progression of early death. The important role of TWIST1 in APL leukemogenesis was first determined by gain- and loss-of-function assays. We then performed and experiments to explore the interaction of TWIST1 and TRIB3 and develop a potential peptide-initiated therapeutic opportunity to protect against early death and induction therapy resistance in patients with APL. We found that the epithelial-mesenchymal transition (EMT)-inducing transcription factor TWIST1 is highly expressed in APL cells and is critical for leukemic cell survival. TWIST1 and TRIB3 were highly coexpressed in APL cells compared with other subtypes of acute myeloid leukemia cells. We subsequently demonstrated that TRIB3 could bind to the WR domain of TWIST1 and contribute to its stabilization by inhibiting its ubiquitination. TRIB3 depletion promoting TWIST1 degradation reverses resistance to induction therapy and improves sensitivity to ATRA. On the basis of a detailed functional screen of synthetic peptides, we discovered a peptide analogous to the TWIST1 WR domain that specifically represses APL cell survival by disrupting the TRIB3/TWIST1 interaction. Our data not only define the essential role of TWIST1 as an EMT-TF in patients with APL but also suggest that disrupting the TRIB3/TWIST1 interaction reverses induction therapy resistance and blocks rapid progression of APL early death. .
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-19-0510