TRIB3促进急性早幼粒细胞白血病疾病进展的作用机制

发布时间：2018-06-26 21:07

本文选题：急性髓细胞白血病 + 急性早幼粒细胞白血病　；参考：《北京协和医学院》2017年硕士论文

【摘要】：急性早幼粒细胞白血病(Acute promyelocytic leukemia,APL)是一种预后凶险的白血病,约占成人急性髓细胞白血病(Acutemyeloidleukemia,AML)的10%。该型白血病出血倾向严重,易并发弥漫性血管内凝血(Diffuse intravascular coagulation,DIC),尤其在化疗时易发生出血,常导致患者早期死亡。APL患者中90%以上都具有特异性T(15,17)染色体易位,第15号染色体的早幼粒细胞白血病(Promyelocyticleukemia,PML)基因和17号染色体的维甲酸受体(RARα)基因易位融合产生融合基因,该融合基因编码融合蛋白PML-RARα。PML-RARα融合蛋白能抑制粒细胞分化,促进APL起始细胞的自我更新,是造成APL发病的罪魁祸首。目前联合使用全反式维甲酸(ATRA)和砷剂(AS203)进行治疗已经大大提高该疾病的治愈率。但是,该一线用药会引发一定的毒副作用,如感染、继发性白血病等,部分患者对靶向PML-RARα的治疗无效,也有部分患者存在治疗后复发的现象,这敦促研究人员进一步探索该疾病的发病机制、寻找潜在的治疗药物。假性激酶Tribbles同源蛋白家族成员(TRIB1、TRIB2和TRIB3)可扮演应激反应感受器的角色,连接各种代谢应激因素参与多种炎症疾病和肿瘤的发生、发展。Trib1和Trib2作为原癌基因促进AML的发病机理及其分子机制研究已被逐步阐明,但Trib3与白血病的关系却鲜有提及。实验室早期研究成果显示,TRIB3不仅促进TGFβ1介导的肿瘤侵袭和迁移,还作为纽带连接代谢危险因素,参与肿瘤发生发展。该研究前期结果表明多种AML亚型患者骨髓组织高表达TRIB3,并且TRIB3表达量与APL疾病进展以及治疗耐受呈正相关。使用三转基因小鼠模型,我们进一步发现,敲除PML-RARα转基因小鼠的Trib3后,小鼠不再发生APL;而敲入Trib3的PML-RARα转基因小鼠APL发生率为100%,并且发病时间明显提前。该研究还显示TRIB3可抑制APL细胞内PML核小体的形成;妨碍APL细胞发生分化;维持APL起始细胞的自我更新能力。这一结果表明TRIB3参与PML-RARα诱发的APL发生和疾病进展。近年来,蛋白质质量控制(Proteinquality control)是肿瘤领域的研究热点之一。蛋白质质量控制失调,例如自噬(Autophagy)或者泛素蛋白酶体降解系统(ubiquitinproteasomesystem,UPS)的功能障碍,导致促肿瘤蛋白堆积,促进肿瘤发生和发展。实验室前期研究结果表明TRIB3通过调节自噬和泛素蛋白酶体的活性影响多种促肿瘤因子的表达。基于以上研究,我们进一步发现,APL细胞中高表达TRIB3通过与PML-RARα/PML发生相互作用,抑制PML-RARα的苏木化、泛素化和降解,维持PML-RARα原癌蛋白的功能。通过解析TRIB3与PML-RARα/PML发生相互作用的具体结构域和关键氨基酸位点,我们发现TRIB3主要与PML-RARα/PML发生苏木化的氨基酸基序结合,并且该相互作用在促APL疾病进程中发挥着关键作用。目前靶向蛋白-蛋白相互作用是药物研发的新兴和热点领域,并已显示出巨大的应用前景和潜在经济价值。因此,靶向TRIB3或者阻断TRIB3与PML-RARα蛋白质间相互作用为APL治疗提供了新的思路和策略。
[Abstract]:Acute promyelocytic leukemia (Acute promyelocytic leukemia, APL) is a malignant leukemia, which accounts for the 10%. in adult acute myelocytic leukemia (Acutemyeloidleukemia, AML), which has a severe bleeding tendency and is prone to diffuse intravascular coagulation (Diffuse intravascular coagulation, DIC), especially during chemotherapy. More than 90% of the patient's early death.APL patients have specific T (15,17) chromosomal translocation. The gene of Promyelocyticleukemia, PML, and the retinoic acid receptor (RAR alpha) gene of chromosome 17 is translocation to produce fusion gene, and the fusion gene encodes the fusion protein PML-RAR a. .PML-RAR alpha fusion protein can inhibit the differentiation of granulocytes and promote self renewal of APL starting cells. It is the culprit of the pathogenesis of APL. Combined use of total trans retinoic acid (ATRA) and arsenic (AS203) therapy has greatly improved the cure rate of the disease. However, this one line drug can cause certain toxic side effects, such as infection, and secondary effects. Some patients have no effect on targeted PML-RAR alpha, and some patients have relapse after treatment. This urges researchers to further explore the pathogenesis of the disease and find potential therapeutic drugs. Pseudokinase Tribbles homologous family members (TRIB1, TRIB2 and TRIB3) can play the role of stress receptor. Role, connecting various metabolic stress factors to participate in the occurrence of a variety of inflammatory diseases and tumors, the development of.Trib1 and Trib2 as a proto oncogene to promote the pathogenesis and molecular mechanism of AML has been gradually clarified, but the relationship between Trib3 and leukemia is rarely mentioned. The early laboratory results showed that TRIB3 not only promoted the swelling of TGF beta 1. Tumor invasion and migration are also linked to metabolic risk factors and participate in the development of tumor. The early results of this study showed that the bone marrow tissues of multiple AML subtypes were highly expressed in TRIB3, and the expression of TRIB3 was positively related to the progression of APL disease and the treatment tolerance. We used three transgenic mice to further discover that PML-RAR alpha was knocked out. After Trib3, APL was no longer occurring in mice, and the incidence of APL in Trib3 PML-RAR alpha transgenic mice was 100%, and the time of onset was obviously earlier. This study also showed that TRIB3 could inhibit the formation of PML nucleosome in APL cells, prevent APL cells from differentiation, and maintain the self-renewal ability of APL starting cells. This result indicates TRIB3. PML-RAR alpha induced APL and disease progression. In recent years, protein quality control (Proteinquality control) is one of the hotspots in the field of cancer. Protein mass control disorders, such as autophagy (Autophagy) or the dysfunction of the ubiquitin proteasome degradation system (ubiquitinproteasomesystem, UPS), lead to the tumor promoting protein reactor The results of early laboratory studies show that TRIB3 affects the expression of various tumor stimulating factors by regulating autophagy and the activity of ubiquitin proteasome. Based on the above study, we further found that high expression of TRIB3 in APL cells can inhibit the hematoxylonination of PML-RAR a by interacting with PML-RAR alpha /PML and inhibiting the hematoxylating of PML-RAR a and ubiquitin The function of PML-RAR alpha proto oncoprotein is maintained and degraded. By analyzing the specific domain and key amino acid loci of the interaction between TRIB3 and PML-RAR alpha /PML, we found that TRIB3 is mainly associated with the amino acid sequence of the hematoxylating of PML-RAR alpha /PML, and the interaction plays a key role in promoting the process of APL disease. Protein protein interaction is a new and hot field in drug research and development, and has shown great potential application and potential economic value. Therefore, targeting TRIB3 or blocking the interaction between TRIB3 and PML-RAR alpha protein provides new ideas and strategies for the treatment of APL.
【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R733.71

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