發(fā)布時(shí)間：2018-06-26 21:07

  本文選題：急性髓細(xì)胞白血病 + 急性早幼粒細(xì)胞白血病　； 參考：《北京協(xié)和醫(yī)學(xué)院》2017年碩士論文

【摘要】：急性早幼粒細(xì)胞白血病(Acute promyelocytic leukemia,APL)是一種預(yù)后兇險(xiǎn)的白血病,約占成人急性髓細(xì)胞白血病(Acutemyeloidleukemia,AML)的10%。該型白血病出血傾向嚴(yán)重,易并發(fā)彌漫性血管內(nèi)凝血(Diffuse intravascular coagulation,DIC),尤其在化療時(shí)易發(fā)生出血,常導(dǎo)致患者早期死亡。APL患者中90%以上都具有特異性T(15,17)染色體易位,第15號(hào)染色體的早幼粒細(xì)胞白血病(Promyelocyticleukemia,PML)基因和17號(hào)染色體的維甲酸受體(RARα)基因易位融合產(chǎn)生融合基因,該融合基因編碼融合蛋白PML-RARα。PML-RARα融合蛋白能抑制粒細(xì)胞分化,促進(jìn)APL起始細(xì)胞的自我更新,是造成APL發(fā)病的罪魁禍?zhǔn)�。目前�?lián)合使用全反式維甲酸(ATRA)和砷劑(AS203)進(jìn)行治療已經(jīng)大大提高該疾病的治愈率。但是,該一線用藥會(huì)引發(fā)一定的毒副作用,如感染、繼發(fā)性白血病等,部分患者對(duì)靶向PML-RARα的治療無(wú)效,也有部分患者存在治療后復(fù)發(fā)的現(xiàn)象,這敦促研究人員進(jìn)一步探索該疾病的發(fā)病機(jī)制、尋找潛在的治療藥物。假性激酶Tribbles同源蛋白家族成員(TRIB1、TRIB2和TRIB3)可扮演應(yīng)激反應(yīng)感受器的角色,連接各種代謝應(yīng)激因素參與多種炎癥疾病和腫瘤的發(fā)生、發(fā)展。Trib1和Trib2作為原癌基因促進(jìn)AML的發(fā)病機(jī)理及其分子機(jī)制研究已被逐步闡明,但Trib3與白血病的關(guān)系卻鮮有提及。實(shí)驗(yàn)室早期研究成果顯示,TRIB3不僅促進(jìn)TGFβ1介導(dǎo)的腫瘤侵襲和遷移,還作為紐帶連接代謝危險(xiǎn)因素,參與腫瘤發(fā)生發(fā)展。該研究前期結(jié)果表明多種AML亞型患者骨髓組織高表達(dá)TRIB3,并且TRIB3表達(dá)量與APL疾病進(jìn)展以及治療耐受呈正相關(guān)。使用三轉(zhuǎn)基因小鼠模型,我們進(jìn)一步發(fā)現(xiàn),敲除PML-RARα轉(zhuǎn)基因小鼠的Trib3后,小鼠不再發(fā)生APL;而敲入Trib3的PML-RARα轉(zhuǎn)基因小鼠APL發(fā)生率為100%,并且發(fā)病時(shí)間明顯提前。該研究還顯示TRIB3可抑制APL細(xì)胞內(nèi)PML核小體的形成;妨礙APL細(xì)胞發(fā)生分化;維持APL起始細(xì)胞的自我更新能力。這一結(jié)果表明TRIB3參與PML-RARα誘發(fā)的APL發(fā)生和疾病進(jìn)展。近年來(lái),蛋白質(zhì)質(zhì)量控制(Proteinquality control)是腫瘤領(lǐng)域的研究熱點(diǎn)之一。蛋白質(zhì)質(zhì)量控制失調(diào),例如自噬(Autophagy)或者泛素蛋白酶體降解系統(tǒng)(ubiquitinproteasomesystem,UPS)的功能障礙,導(dǎo)致促腫瘤蛋白堆積,促進(jìn)腫瘤發(fā)生和發(fā)展。實(shí)驗(yàn)室前期研究結(jié)果表明TRIB3通過(guò)調(diào)節(jié)自噬和泛素蛋白酶體的活性影響多種促腫瘤因子的表達(dá)�；谝陨涎芯�,我們進(jìn)一步發(fā)現(xiàn),APL細(xì)胞中高表達(dá)TRIB3通過(guò)與PML-RARα/PML發(fā)生相互作用,抑制PML-RARα的蘇木化、泛素化和降解,維持PML-RARα原癌蛋白的功能。通過(guò)解析TRIB3與PML-RARα/PML發(fā)生相互作用的具體結(jié)構(gòu)域和關(guān)鍵氨基酸位點(diǎn),我們發(fā)現(xiàn)TRIB3主要與PML-RARα/PML發(fā)生蘇木化的氨基酸基序結(jié)合,并且該相互作用在促APL疾病進(jìn)程中發(fā)揮著關(guān)鍵作用。目前靶向蛋白-蛋白相互作用是藥物研發(fā)的新興和熱點(diǎn)領(lǐng)域,并已顯示出巨大的應(yīng)用前景和潛在經(jīng)濟(jì)價(jià)值。因此,靶向TRIB3或者阻斷TRIB3與PML-RARα蛋白質(zhì)間相互作用為APL治療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.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R733.71

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