TRIB3 stabilizes high TWIST1 expression to promote rapid APL progression & ATRA resistance

Purpose: The resistance to differentiation therapy and early death caused by fatal bleeding endangers the health of a significant proportion of APL patients. This study aims to investigate the molecular mechanisms of ATRA resistance and uncover new potential therapeutic strategies to block the rapid progression of early death. Experimental design: 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. Results: 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 co-expressed in APL cells compared with other subtypes of acute myeloid leukemia (AML) 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. Based on 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. Conclusions: Our data not only define the essential role of TWIST1 as an EMT-TF in APL patients but also suggest that disrupting the TRIB3/TWIST1 interaction reverses induction therapy resistance and blocks rapid progression of APL early death. Translational Relevance This study was designed to improve the treatment for high-risk APL patients. This proportion of APL patients continued to suffer from early fatal bleeding and leukemic extramedullary infiltration, which remains the most important challenge and the largest obstacle to curing all APL patients. We demonstrate that the unique EMT-inducing transcription factor TWIST1 is significantly highly expressed in APL and governs the survival of APL cells. We show that TRIB3 interacts with TWIST1 and stabilizes high TWIST1 expression by repressing TWIST1 ubiquitination. Our data also suggest that a peptide similar to the WR domain disturbs the TRIB3/TWIST1 interaction, impairs rapid progression during the early death of APL and reverses resistance to ATRA therapy. These results reveal the important role of a specific oncogenic transcriptional factor, TWIST1, in APL leukemogenesis and suggest a potential peptide-initiated therapeutic opportunity to protect against early death and induction therapy resistance in patients with APL.