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

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TRIB3 Stabilizes High TWIST1 Expression to Promote Rapid APL Progression and ATRA Resistance Author Manuscript Published OnlineFirst on June 24, 2019; DOI: 10.1158/1078-0432.CCR-19-0510 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. TRIB3 Stabilizes High TWIST1 Expression to Promote Rapid APL Progression and ATRA Resistance Jian Lin1, 3, Wu Zhang1, 3, *, Li-Ting Niu1, Yong-Mei Zhu1, Xiang-Qin Weng1, Yan Sheng1, Jiang Zhu1 and Jie Xu1, 2, * 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, 197 Ruijin Er Road, Shanghai 200025, China. 2Translational Medicine Ward, Department of Hematology, Rui-Jin Hospital, Shanghai 200025, China. 3These authors contributed equally to this work. *Correspondence: Jie Xu, State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology Rui-Jin Hospital, affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China. E-mail: nbxujie1011@163.com; and Wu Zhang, State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology Rui-Jin Hospital, affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China. E-mail: zhangwuruijin@163.com; Running title: TRIB3 stabilizes TWIST1 to promote APL progression Key words: Acute promyelocytic leukemia; TWIST1; TRIB3; Early death; ATRA-resistance Conflict of interest statement: The authors declare no potential conflicts of interest. 1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 24, 2019; DOI: 10.1158/1078-0432.CCR-19-0510 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract 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. 2 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 24, 2019; DOI: 10.1158/1078-0432.CCR-19-0510 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 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. 3 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 24, 2019; DOI: 10.1158/1078-0432.CCR-19-0510 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Acute promyelocytic leukemia (APL), which accounts for 10-15% of 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) (1,2). 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 (3). 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 (4-6). Importantly, APL patients with a high white blood cell count face an increased risk of early HD (7). Furthermore, resistance to ATRA/ATO treatment with PML-RARα mutations still remains a therapeutic challenge for 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 death and overcome resistance. Oncogenic transcription factors play an important role in the development of hematological malignancy (8,9). The dysregulation of epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs), including SNAI1/SNAI2, ZEB1/ZEB2 and TWIST1/TWIST2, has also been explored within the context of the aggressive invasion, chemoresistance and poor prognosis of acute myeloid leukemia (AML) (10-12). TWIST1, a highly conserved basic helix-loop-helix (bHLH) protein, is a well-characterized EMT-TF that plays a critical role in embryonic development and cancer metastasis (13,14). Recent studies have shown that TWIST1 is overexpressed in primary AML samples (15). Our previous study reported that high expression of TWIST1 in AML contributes to extramedullary infiltration and promotes leukemic aggressiveness (16). These findings strongly suggest that 4 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 24, 2019; DOI: 10.1158/1078-0432.CCR-19-0510 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. disruption of TWIST1 is involved in leukemogenesis. However, the prognosis of AML patients with high TWIST1 expression is controversial based on several reports (15,17). These conflicting reports likely occurred because TWIST1 expression in AML is heterogeneous (18). TWIST1 expression is higher in APL, an intriguing AML subtype in which successful clinical tumor differentiation-induction therapy has been applied and for which the clinical phenotype is inconsistent with the expression level of TWIST1 (15,18). In this study, we demonstrate that the EMT-TF 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 contribute to a better understanding of the molecular mechanism of APL pathogenesis and will allow for designing more effective therapeutic strategies to block the rapid progression of early death and overcome resistance. Materials and Methods Cells and mice Leukemic cell lines were cultured in RPMI-1640 medium (Invitrogen, Grand Island, USA) supplemented with 10% FBS (Invitrogen, Grand Island, USA), and HEK293T cells were grown in DMEM (Invitrogen, Grand Island, USA) supplemented with 10% FBS. All cell lines, including NB4-R1 and PR9 cell line, were obtained from the Shanghai Institute of Hematology as previously described (19-21). NB4-R1, a de novo ATRA-resistant cell line isolated from parental NB4 cells, was obtained from Dr. Michel Lanotte (Hospital Saint Louis, Paris, France) (22). HMRP8-PML-RARα 5 Downloaded from clincancerres.aacrjournals.org on October 1, 2021.
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