American Association for Cancer Research
10780432ccr190510-sup-217025_3_supp_5592865_ptmmmt.docx (11.13 MB)

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

Download (11.13 MB)
journal contribution
posted on 2023-03-31, 21:08 authored by Jian Lin, Wu Zhang, Li-Ting Niu, Yong-Mei Zhu, Xiang-Qin Weng, Yan Sheng, Jiang Zhu, Jie Xu

Supplementary Figure 1. TWIST1 was highly expressed in APL cells. Supplementary Figure 2. High TWIST1 expression promotes APL progression. Supplementary Figure 3. TRIB3 interacts with TWIST1 in APL cells. Supplementary Figure 4. TRIB3 inhibition promotes TWIST1 degradation and reverses resistance to ATRA therapy. Supplementary Figure 5. The WR domain of TWIST1 is required for the binging of TWIST1/TRIB3 complex and TWIST1 stabilization. Supplementary Figure 6. Competitive inhibition of the TRIB3/TWIST1 interaction impairs rapid progression during the early death of APL.


National Natural Science Foundation of China



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-trans 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 in vivo and in vitro 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.See related commentary by Peeke and Gritsman, p. 6018