维甲酸（RA）诱导分化治疗急性早幼粒细胞白血病（APL），显著提高了APL的缓解率及预后，是肿瘤诱导分化治疗的典范。然而，APL存在复发耐药的问题，且少数变异型APL对维甲酸原发耐药，如PLZF-RARA、STAT5b-RARA APL，耐药机制尚不明确。GTF2I-RARA是本研究组从一例对RA不敏感的APL患者中发现的新型融合基因。在探索该型APL对RA耐药的机制的过程中，我们发现转染GTF2I-RARA后 ，RARA的蛋白水平明显减低，泛素化水平增高，提示GTF2I-RARA促进了RARA的泛素化降解。应用蛋白酶体抑制剂MG132靶向抑制RARA的主要降解途径——泛素-蛋白酶体系统，可稳定RARA蛋白，协同RA诱导分化。本项目拟深入探讨硼替佐米联合RA在GTF2I-RARA APL模式细胞株及动物模型中的诱导分化和凋亡的作用及其机制，对该型APL的治疗有重要意义。

Retinoic acid (RA) has achieved great success in inducing differentiation of acute promyelocytic leukemia (APL) resulting in high remission rate and improved prognosis, and has become a paradigm of cancer differentiation therapy. However, relapses and RA insensitivity occur in APL, and a few variant APL, such as PLZF-RARA and STAT5b-RARA, demonstrate ATRA resistance. The underlying mechanism for RA resistance is not yet clear. GTF2I-RARA is a novel RARA fusion gene isolated from an RA-insensitive APL patient by our group. Our previous work showed GTF2I-RARA promoted RARA ubiquitination, decreased RARA protein level, thus contributed to RA resistance. Targeting the ubiquitin proteasome pathway (UPP), which is mainly responsible for RARA degradation, by proteasome inhibitor MG132 can stabilize RARA, and synergize with RA in inducing differentiation. In this project, we aim to further study the synergistic effect of bortezomib and RA in inducing differentiation and apoptosis, both in vitro and in vivo, and its underlying mechanism. This study will not only gain new insights into RA resistance, but also provide therapeutic strategies for GTF2I-RARA APL.