Abstract 4406: TRIB3 stabilizes high TWIST1 expression to promote rapid APL progression & ATRA resistance

Abstract

Abstract Acute promyelocytic leukemia (APL), which accounts for 10-15% of acute myeloid leukemia (AML) cases, is characterized by the t (15; 17) chromosomal translocation and is now highly curable by the combination of granulocytic differentiation induction and the PML-RARα oncoprotein-targeted agents all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Despite the striking molecular complete remission (CR) and the very few cases of relapse associated with ATRA/ATO-based regimens, mortality events typically result from early fatal bleeding, which remains the most important challenge and the largest obstacle to curing all APL patients. For instance, several studies have reported that the risk of early hemorrhagic death (HD) reaches an incidence of 10-20% during the first month of induction. Importantly, APL patients with a high white blood cell count face an increased risk of early HD. Furthermore, differentiation syndrome and resistance to ATRA/ATO treatment with PML-RARα mutations still endanger the health of a significant proportion of APL patients. Thus, we need to better understand the molecular mechanism of APL pathogenesis and design more effective therapeutic strategies to block the rapid progression of early HD and overcome resistance. Oncogenic transcription factors play an important role in the development of hematological malignancy. The dysregulation of epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs), including SNAI1/SNAI2, ZEB1/ZEB2 and TWIST1/TWIST2, which are closely related to malignant progression in solid tumors, has also been explored in the context of the aggressive invasion, chemoresistance and poor prognosis of AML. In this study, we found through two database (TCGA and E-MTAB-344) gene expression searches and detailed functional verification that the EMT-TF 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 AML. We subsequently demonstrated that TRIB3 could bind the bHLH and WR domains of TWIST1 and stabilize TWIST1 by inhibiting the ubiquitination of the TWIST1 protein. Based on a detailed analysis of a functional screen of synthetic peptides, we discovered a peptide analogous to the previously reported TWIST1 WR domain, which rapidly and specifically represses APL cell survival through disrupting the TRIB3/TWIST1 interaction. 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 rapid proteolysis therapeutic opportunity to protect against early death and induction therapy resistance in patients with APL. Citation Format: Wu Zhang, Jian Lin, Jie Xu. TRIB3 stabilizes high TWIST1 expression to promote rapid APL progression & ATRA resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4406.