本文選題：骨髓增殖性腫瘤 + JAK2V617F　； 參考：《山東大學(xué)》2016年博士論文

【摘要】：骨髓增殖性腫瘤(MPN)是骨髓持續(xù)克隆增殖性造血干細(xì)胞疾病。經(jīng)典的BCR-ABL陰性MPN包括真性紅細(xì)胞增多癥(PV)、原發(fā)性血小板增多癥(ET)和原發(fā)性骨髓纖維化(PMF)。血栓栓塞是MPN患者死亡的主要原因,并嚴(yán)重影響患者的生存質(zhì)量,早期及時(shí)的發(fā)現(xiàn)血栓并相應(yīng)干預(yù)將大大的降低患者的死亡率。JAK2V617F基因突變?yōu)榻?jīng)典的BCR-ABL陰性MPN的特征性改變,除此以外,還發(fā)現(xiàn)有CALR及MPL基因突變。JAK2V617F、CALR及MPL基因突變與血栓性疾病的關(guān)系國(guó)內(nèi)雖有研究,但均為回顧性。本研究檢測(cè)了MPN患者的JAK2V617F、CALR及MPL基因突變率,跟蹤2年觀察其血栓性疾病的發(fā)生率,并通過(guò)檢測(cè)MPN患者單個(gè)核細(xì)胞的pSTAT3、TNF-α mRNA和IL-6 mRNA的表達(dá),對(duì)MPN并發(fā)血栓的發(fā)病機(jī)制做了進(jìn)一步的深入研究。第一部分MPN患者JAK2V617F、CALR和MPL基因突變率及其臨床特征研究(基線研究)[研究目的]檢測(cè)MPN患者JAK2V617F、CALR和MPL基因突變率并調(diào)查與血栓形成相關(guān)的臨床特征。[研究方法](1)研究對(duì)象共3組,病例組為2013年9月至2014年4月確診為MPN且沒(méi)有血栓并發(fā)癥的患者,共68例(病例組,n=68)；血栓組為同期確診為動(dòng)脈或靜脈血栓形成者,但無(wú)血液疾病,共65例(血栓組,n=65)；對(duì)照組為同期健康體檢者或血液內(nèi)科病情穩(wěn)定的非MPN患者,沒(méi)有血栓并發(fā)癥,共68例(對(duì)照組,n=68)。(2)記錄所有受試者的年齡、性別、居住地、職業(yè)等一般資料及既往史、吸煙史、酗酒史等,采集所有研究對(duì)象的血壓值、空腹血糖值、血低密度脂蛋白濃度、高密度脂蛋白濃度、膽固醇濃度值、身體質(zhì)量指數(shù)等與血栓形成有關(guān)的危險(xiǎn)因子及凝血常規(guī)和血常規(guī)等。(3)采集所有研究對(duì)象隔夜空腹肘靜脈血各3 ml用于檢測(cè)JAK2V617F、CALR、 MPL基因突變。采集所有研究對(duì)象隔夜空腹肘靜脈血足量用于檢測(cè)空腹血糖、血脂譜、凝血常規(guī)和血常規(guī)等指標(biāo)。(4)用人JAK2V617F基因變異檢測(cè)試劑盒提取血細(xì)胞中的基因組DNA,采用LightCycler 480熒光PCR基因擴(kuò)增檢測(cè)儀進(jìn)行PCR擴(kuò)增,用AB13730型基因分析儀測(cè)序,輸出結(jié)果。[結(jié)果](1)對(duì)三組研究對(duì)象進(jìn)行JAK2V617F基因突變進(jìn)行檢測(cè),68例MPN患者有46例發(fā)生JAK2V617F基因突變,突變率為67.65%。其中ET患者24例,突變率為64.86%,PV患者19例,突變率為82.61%,IMF患者3例,突變率為37.5%。68例對(duì)照組中JAK2V617F突變陽(yáng)性為1例,突變率為1.47%。MPN患者組JAK2V617F突變率顯著高于對(duì)照組(P0.05)。65例血栓組中JAK2V617F突變陽(yáng)性為8例,突變率為12.31%。MPN患者組JAK2V617F突變率顯著高于血栓組(P0.05)。血栓組JAK2V617F突變率顯著高于對(duì)照組(P0.05)。對(duì)三組研究對(duì)象進(jìn)行CALR基因突變進(jìn)行檢測(cè)。68例MPN患者有12例發(fā)生CALR基因突變,突變率為17.65%,其中包括ET患者10例,PV患者0例,PMF患者2例。68例對(duì)照組中CALR突變陽(yáng)性為0例。MPN患者組與對(duì)照組比較P0.05,差異有統(tǒng)計(jì)學(xué)意義。65例血栓組CALR突變陽(yáng)性為0例。MPN患者組與血栓組比較P0.05,差異有統(tǒng)計(jì)學(xué)意義。對(duì)三組研究對(duì)象進(jìn)行MPL基因突變進(jìn)行檢測(cè)。68例MPN患者有3例發(fā)生MPL基因突變,突變率為4.41%,其中包括ET患者2例,PV患者0例,IMF患者1例。68例對(duì)照組中MPL突變陽(yáng)性為0例。MPN患者組與對(duì)照組比較P0.05,差異有統(tǒng)計(jì)學(xué)意義。65例血栓組MPL突變陽(yáng)性為0例。MPN患者組與血栓組比較P0.05,差異有統(tǒng)計(jì)學(xué)意義。MPN患者中三種基因全陰性的7例,占10.29%,三種突變沒(méi)有同時(shí)出現(xiàn)。(2)對(duì)病例組JAK2V617F陽(yáng)性患者與JAK2V617F陰性患者間血栓風(fēng)險(xiǎn)因子的比較,JAK2V617F陽(yáng)性MPN患者與JAK2V617F陰性MPN患者間的收縮壓、舒張壓、空腹血糖值和血脂譜值等均無(wú)顯著性統(tǒng)計(jì)學(xué)差異(P0.05)。對(duì)病例組CALR陽(yáng)性患者與CALR陰性患者間血栓風(fēng)險(xiǎn)因子的比較,除了空腹血糖外,兩組患者間的收縮壓、舒張壓、LDL、HDL、BMI、膽固醇等血栓風(fēng)險(xiǎn)因子均無(wú)顯著性統(tǒng)計(jì)學(xué)差異。比較病例組MPL陽(yáng)性患者與MPL陰性患者間血栓風(fēng)險(xiǎn)因子的比較,兩組患者間的空腹血糖、收縮壓、舒張壓、LDL、HDL、BMI、膽固醇等血栓風(fēng)險(xiǎn)因子均無(wú)顯著性統(tǒng)計(jì)學(xué)差異。(3)病例組PT值[(16.94±2.07)s]顯著高于對(duì)照組[(12.26±±0.96)s](P0.05)：病例組APTT值[(59.26±12.38)s]顯著高于對(duì)照組[(30.73±3.13)s](P0.05)；病例組TT值[(16.58±1.75)s]顯著高于對(duì)照組[(12.53±1.07)s](P0.05);病例組FIB值[(3.02±±0.58)g/L]顯著低于對(duì)照組[(3.36±±0.49)g/L](P0.05)。病例組中JAK2V617F突變陽(yáng)性患者的PT為(17.87+1.56)s]顯著高于JAK2V617F突變陰性患者[(15.00±1.60)s(P0.05);JAK2V617F突變陽(yáng)性患者的APTT[(64.22±10.82)s]顯著高于JAK2V617F突變陰性患者[(48.91±8.49)s (P0.05); JAK2V617F突變陽(yáng)性患者的TT[(16.98±1.642)s]顯著高于JAK2V617F突變陰性患者[(15.78±1.72)s(P0.05)。病例組中的CALR突變陰性患者與CARL突變陽(yáng)性患者間的PT、APTT、TT、FIB均無(wú)顯著性統(tǒng)計(jì)學(xué)差異,且病例組中的MPL突變陰性患者與MPL突變陽(yáng)性患者間的PT、APTT、TT、FIB均無(wú)顯著性統(tǒng)計(jì)學(xué)差異。[結(jié)論及意義]MPN患者有顯著較高的JAK2V617F、CALR和MPL基因突變率;MPN患者中JAK2V617F基因突變陽(yáng)性與陰性患者間的已知血栓形成風(fēng)險(xiǎn)因子無(wú)顯著差異;MPN患者中JAK2V617F基因突變陽(yáng)性患者凝血功能較陰性患者顯著異常。第二部分MPN患者2年內(nèi)血栓事件發(fā)生的隨訪及其機(jī)制研究[研究目的]探討MPN患者JAK2V617F、CALR及MPL基因突變與血栓性疾病發(fā)生的相關(guān)性及其機(jī)制研究。[研究方法](1)研究對(duì)象為第一部分的病例組和對(duì)照組。自入組之日起,電話或門診隨訪所有研究對(duì)象至少每月兩次,詢問(wèn)并記錄所有研究對(duì)象的詳細(xì)病史,尤其是與血栓事件及血液病發(fā)生相關(guān)的病史,以及血壓值、體重及期間的血液檢測(cè)指標(biāo)等。共隨訪2年,沒(méi)有失訪者,最晚者隨訪至2016年4月。(2)分離MPN組患者外周血單個(gè)核細(xì)胞,提取細(xì)胞質(zhì)總蛋白,免疫印跡法檢測(cè)pSTAT3蛋白表達(dá),提取外周血單個(gè)核細(xì)胞mRNA, RQ-PCR檢測(cè)TNF-α mRNA. IL-6 mRNA的表達(dá)。[結(jié)果](1)追蹤患者2年發(fā)生血栓性疾病情況。68例MPN患者中有26例患者發(fā)生血栓,血栓發(fā)生率為38.24%。對(duì)照組有2例發(fā)生血栓,發(fā)生率為2.94%,病例組的血栓發(fā)生率顯著高于對(duì)照組(P0.05)。病例組JAK2V617F陽(yáng)性患者中血栓患者為47.83%(22/46),非血栓患者為52.17%(24/46)；病例組JAK2V617F陰性患者中血栓患者為18.18%(4/22),非血栓患者為81.82%(18/22), JAK2V617F陽(yáng)性MPN患者的血栓發(fā)生率顯著高于JAK2V617F陰性MPN患者(P=0.019)。CALR和MPL基因突變陽(yáng)性MPN患者的血栓發(fā)生率均為0。(2)病例組PT值[(17.04±2.15)s]顯著高于對(duì)照組[(12.18±0.88)s](P0.05)；病例組APTT值[(58.15±12.49)s]顯著高于對(duì)照組[(30.87±3.00)s](P0.05)；病例組TT值[(17.59±2.81)s]顯著高于對(duì)照組[(12.47±1.04)s](P0.05)；病例組FIB值[(3.05+0.56)g/L]顯著低于對(duì)照組[(3.33±0.44)g/L](P0.05)。(3)ET患者中血栓患者PLT值[(840.15±48.60)×109/L],顯著高于ET患者中非血栓患者[(809.46±36.98)×109/L](P0.05)。病例組中血栓患者TT為(18.85±2.72)s顯著高于非血栓患者(16.81±2.60)s(P0.05)。(4)對(duì)病例組患者與對(duì)照組研究對(duì)象間血栓風(fēng)險(xiǎn)因子的比較：隨訪2年后,病例組患者與對(duì)照組間的收縮壓值(P0.05)、舒張壓值(P0.05)、空腹血糖值(P0.05)、血脂譜值(P0.05)均無(wú)顯著性統(tǒng)計(jì)學(xué)差異。(5)對(duì)病例組血栓患者與非血栓患者間血栓風(fēng)險(xiǎn)因子的比較：隨訪2年后,病例組中血栓患者與非血栓患者間的收縮壓值(P0.05)、舒張壓值(P0.05)空腹血糖值(P0.05)、血脂譜值(P0.05)均無(wú)顯著性統(tǒng)計(jì)學(xué)差異。(6)MPN患者血栓并發(fā)癥與外周血單個(gè)核細(xì)胞中P-STAT3的表達(dá)間的關(guān)系：與JAK2V617F突變陰性的MPN患者相比,JAK2V617F突變陽(yáng)性的患者中P-STAT3蛋白灰度值顯著較高(P0.05)；與無(wú)血栓并發(fā)癥的MPN患者相比,發(fā)生血栓并發(fā)癥的MPN患者有顯著較高的P-STAT5蛋白表達(dá)灰度值(P0.05)。JAK2V617F突變陽(yáng)性且并發(fā)血栓的MPN患者的P-STAT3蛋白表達(dá)灰度值顯著較高(P0.05)。(7)MPN患者血栓并發(fā)癥與外周血單個(gè)核細(xì)胞中IL-6 mRNA的表達(dá)間的關(guān)系：與JAK2V617F突變陰性的MPN患者相比,JAK2V617F突變陽(yáng)性的患者中IL-6mRNA相對(duì)值顯著較高(P0.05)；與無(wú)血栓并發(fā)癥的MPN患者相比,發(fā)生血栓并發(fā)癥的MPN患者有顯著較高的IL-6 mRNA相對(duì)值(P0.05);JAK2V617F突變陽(yáng)性且并發(fā)血栓的MPN患者的IL-6 mRNA相對(duì)值顯著較高(P0.05)。[結(jié)論及意義]MPN患者中JAK2V617F基因突變陽(yáng)性患者易發(fā)血栓事件；JAK2V617F基因突變陽(yáng)性是MPN患者發(fā)生血栓事件的原因；MPN患者JAK2V617F基因突變陽(yáng)性可能通過(guò)某種信號(hào)轉(zhuǎn)導(dǎo)路徑影響致凝血常規(guī)檢測(cè)結(jié)果顯著異常,最終導(dǎo)致血栓事件發(fā)生；IL-6相關(guān)的、經(jīng)STAT3活化的JAK-STAT信號(hào)路徑可能是JAK2V617F突變陽(yáng)性的MPN患者血栓并發(fā)癥的機(jī)制之一。本研究的創(chuàng)新點(diǎn)1、本研究檢測(cè)了所有研究對(duì)象的JAK2V617F、CALR及MPL基因的突變率,通過(guò)設(shè)立對(duì)照組和2年的跟蹤隨訪,對(duì)MPN患者血栓發(fā)生與JAK2V617F、 CALR及MPL基因突變陽(yáng)性間的關(guān)系做了前瞻性的研究,發(fā)現(xiàn)MPN患者中JAK2V617F基因突變陽(yáng)性患者易發(fā)血栓事件,CALR及MPL基因突變突變沒(méi)有增加MPN患者的血栓發(fā)生率。2、通過(guò)檢測(cè)MPN患者單個(gè)核細(xì)胞的pSTAT3、TNF-α mRNA、IL-6 mRNA的表達(dá),提示IL-6相關(guān)的、經(jīng)STAT3活化的JAK-STAT信號(hào)路徑可能是JAK2V617F突變陽(yáng)性的MPN患者發(fā)生血栓并發(fā)癥的機(jī)制之一。
[Abstract]:Myeloproliferative tumor (MPN) is a persistent and proliferative hematopoietic stem cell disease of the bone marrow. The classic BCR-ABL negative MPN includes true erythrocytosis (PV), primary thrombocythemia (ET) and primary myelofibrosis (PMF). Thromboembolism is the main cause of death in MPN patients and seriously affects the patient's quality of life, early and timely. The discovery of thrombus and corresponding intervention will greatly reduce the death rate of the patient's.JAK2V617F gene to the classic BCR-ABL negative MPN. In addition, there are also CALR and MPL gene mutations.JAK2V617F, and the relationship between the CALR and MPL gene mutations and thrombotic diseases in China, although they are all reviewed. This study detected M The mutation rate of JAK2V617F, CALR and MPL gene in PN patients was followed up for 2 years to observe the incidence of thrombotic diseases, and the pathogenesis of MPN concurrent thrombus was further studied by detecting the expression of pSTAT3, TNF- a mRNA and IL-6 mRNA in the mononuclear cells of the patients with MPN. The clinical feature study (baseline study) [Objective] to detect the mutation rate of JAK2V617F, CALR and MPL genes in MPN patients and to investigate the clinical features associated with thrombosis. [research methods] (1) a total of 3 subjects were studied in a case group of 68 patients (case group, n=68), and 68 cases (case group, n=68). The group was diagnosed as an arterial or venous thrombosis in the same period, but there were no blood diseases, 65 cases (thrombus group, n=65), and the control group was a healthy physical examination or a non MPN patient with stable condition in the blood department. There was no thrombus complication, 68 cases (control group, n=68). (2) record all the subjects' age, sex, residence, occupation and so on. History, smoking history, drinking history, etc., collected all the subjects' blood pressure, fasting blood glucose, HDL concentration, HDL concentration, cholesterol concentration, body mass index and other risk factors related to thrombosis, clotting routine and blood routine. (3) all subjects were collected on the overnight empty abdominal elbow vein blood of 3. Ml was used to detect JAK2V617F, CALR, and MPL mutations. All subjects were used to measure the blood glucose, blood lipid spectrum, blood clotting routine and blood routine. (4) the gene group DNA in blood cells was extracted by the JAK2V617F gene mutation detection kit, and the LightCycler 480 fluorescent PCR gene amplification detector was used. PCR amplification, AB13730 gene analyzer sequencing, output results. [results] (1) three groups of subjects were detected JAK2V617F gene mutation, 68 cases of MPN patients with JAK2V617F gene mutation, the mutation rate was 67.65%. of 24 cases of ET patients, the mutation rate was 64.86%, PV patients 19 cases, the mutation rate was 82.61%, IMF patients 3 cases, mutation In the control group, the rate of JAK2V617F mutation was 1 cases in the control group, and the mutation rate was higher than that of the control group, the JAK2V617F mutation rate was significantly higher than that of the control group (P0.05), the JAK2V617F mutation was 8 in the.65 thrombus group, and the mutation rate was significantly higher than that in the blood thrombus group (P0.05) in the group of 12.31%.MPN patients. The JAK2V617F mutation rate in the thrombus group was significantly higher than that in the group of 37.5%.68. Control group (P0.05). CALR gene mutations in three groups of subjects were detected in 12 cases of.68 cases MPN mutation, the mutation rate was 17.65%, including 10 cases of ET patients, 0 cases of PV patients, 2 cases of PMF patients in.68 case control group, 0 cases of.MPN patients were compared with the control group, the difference was statistically significant. The CALR mutation in the thrombus group was 0 cases of.MPN patients and the thrombus group was P0.05, the difference was statistically significant. 3 cases of MPN patients in the three groups of subjects were detected with MPL gene mutation, the mutation rate was 4.41%, including 2 cases of ET patients, 0 cases of PV patients, 1.68 case control group of IMF patients, 0 MPL mutations were 0. Cases of.MPN patients were compared with the control group P0.05, the difference was statistically significant in.65 cases, MPL mutation was positive in 0 cases of.MPN patients and P0.05 in thrombus group. The difference was statistically significant in 7 cases of all negative three genes in.MPN patients, accounting for 10.29%, and three kinds of mutations did not appear simultaneously. (2) the case group JAK2V617F positive patients and JAK2V617F negative There was no significant difference in systolic pressure, diastolic blood pressure, fasting blood glucose and blood lipid profiles between JAK2V617F positive MPN patients and JAK2V617F negative MPN patients (P0.05). Two groups of patients with CALR positive patients and CALR negative patients were compared with fasting blood glucose. There was no significant difference in systolic blood pressure, diastolic pressure, LDL, HDL, BMI, cholesterol and other thrombotic risk factors. Compared with the thrombus risk factors between the MPL positive patients and the MPL negative patients, there was no significant difference between the two groups of fasting blood glucose, systolic pressure, diastolic pressure, LDL, HDL, BMI, cholesterol and other thrombotic risk factors. (3) the PT value of the case group [(16.94 + 2.07) s] was significantly higher than that of the control group (12.26 + 0.96) s] (P0.05): the APTT value of the case group was significantly higher than that of the control group [(30.73 + 3.13) s] (P0.05), and the TT value [(16.58 + 1.75) s] of the case group was significantly higher than that of the control group [12.53 + 1.07) s] (P0.05). .36 + 0.49) g/L] (P0.05). The PT of JAK2V617F mutation positive patients in the case group was significantly higher than that of JAK2V617F mutation negative patients [(15 + 1.60) s (P0.05), JAK2V617F mutation positive patients' APTT[(64.22 + 10.82) was significantly higher than that of the negative patients [48.91 + 8.49); 16. 98 + 1.642) s] was significantly higher than that of JAK2V617F mutant negative patients [(15.78 + 1.72) s (P0.05). There was no significant difference in PT, APTT, TT, FIB between the CALR mutation negative patients and the CARL positive patients in the case group, and there was no significant difference between the MPL and the MPL mutations. [Conclusion and significance]MPN patients have significantly higher JAK2V617F, CALR and MPL mutation rates; there is no significant difference in the known thromboformation risk factors between the JAK2V617F gene mutation positive and negative patients in MPN patients, and there is a significant abnormal coagulation function in patients with JAK2V617F gene mutation in MPN patients. Second partial MPN patients 2 Follow up and mechanism study of thrombus events during the year [Objective] to investigate the correlation and mechanism of JAK2V617F, CALR, and MPL mutations in MPN patients with thrombotic diseases. [1] the research object is the first part of the case group and the control group. From the day of entry, all the subjects are followed up by telephone or outpatient service. Two times a month, we asked and recorded the detailed history of all the subjects, especially the history of thrombosis and hematological diseases, and the blood pressure, weight and blood test indexes during the period of 2 years. No missing persons were followed up to April 2016. (2) isolated peripheral blood mononuclear cells from the MPN group were isolated and the cells were extracted. Total protein, immunoblotting was used to detect the expression of pSTAT3 protein, mRNA in peripheral blood mononuclear cells, and the expression of TNF- alpha mRNA. IL-6 mRNA in peripheral blood. [results] (1) 26 cases of patients with thrombotic disease in 2 years were traced and 26 patients had thrombus. The incidence of thrombosis was 2 cases in the control group of 38.24%. control, and the incidence was 2. .94%, the incidence of thrombus in the case group was significantly higher than that in the control group (P0.05). The thrombus patients in the case group JAK2V617F positive patients were 47.83% (22/46), the non thrombus patients were 52.17% (24/46); the thrombus patients in the case group JAK2V617F negative patients were 18.18% (4/22), the non thrombus patients were 81.82% (18/22), and the thrombus incidence was significant in the JAK2V617F positive MPN patients. The incidence of thrombus in the.CALR and MPL positive MPN patients with JAK2V617F negative MPN (P=0.019) was 0. (2) ((17.04 + 2.15) s] significantly higher than that of the control group [(12.18 + 0.88) s] (P0.05)), and the APTT value [(58.15 + 12.49)) of the case group was significantly higher than that of the Group [(30.87 + 3)]. Higher than the control group [(12.47 + 1.04) s] (P0.05)), the FIB value of the case group [(3.05+0.56) g/L] was significantly lower than that of the control group [(3.33 + 0.44) g/L] (P0.05). (3) the thrombotic patients in ET patients [(840.15 + 48.60) * 109/L], significantly higher than those in the ET patients [(809.46 + 36.98) * 109/L]]. In patients with non thrombus (16.81 + 2.60) s (P0.05). (4) a comparison of thrombus risk factors between the patients and the control group: after 2 years of follow-up, the systolic pressure (P0.05), diastolic blood pressure (P0.05), fasting blood glucose (P0.05) and blood lipid (P0.05) between the patients and the control group had no significant difference. (5) thrombosis in the case group. Comparison of thrombus risk factors between patients and non thrombotic patients: after 2 years of follow-up, the systolic pressure value (P0.05), diastolic blood pressure (P0.05) fasting blood glucose (P0.05) and blood lipid (P0.05) in patients with thrombus were not significantly different in the case group. (6) thrombus complication in MPN patients and P-STAT3 in peripheral blood mononuclear cells Relationship between expression: the gray value of P-STAT3 protein was significantly higher in patients with JAK2V617F mutations than in patients with negative JAK2V617F mutations (P0.05). Compared with MPN patients without thrombotic complications, the MPN patients with thrombotic complications had a significantly higher level of P-STAT5 protein expression (P0.05).JAK2V617F mutation positive and concurrence. The gray value of P-STAT3 protein expression in MPN patients with thrombus was significantly higher (P0.05). (7) the relationship between thrombus complications and the expression of IL-6 mRNA in peripheral blood mononuclear cells in MPN patients: the relative value of IL-6mRNA was significantly higher in patients with positive JAK2V617F mutations than in MPN patients with negative JAK2V617F mutations (P0.05); M with thrombotic complications Compared to patients with PN, the MPN patients with thrombotic complications had a significant higher relative value of IL-6 mRNA (P0.05), and the IL-6 mRNA relative value of the MPN patients with positive JAK2V617F mutation and thrombus was significantly higher (P0.05). [Conclusion and]MPN patients with JAK2V617F genes mutation positive patients were prone to thrombosis; The cause of thrombus events in patients; the JAK2V617F gene mutation in MPN patients may be significantly abnormal through some signal transduction pathway and eventually leads to thrombus events; IL-6 related, STAT3 activated JAK-STAT signaling pathway may be a thrombotic complication of MPN patients with positive JAK2V617F mutation. One of the innovative points of this study. 1. This study examined the mutation rates of the JAK2V617F, CALR and MPL genes in all the subjects. By setting up a control group and a follow-up follow-up of 2 years, a prospective study was made on the relationship between thrombosis and the positive mutations of the JAK2V617F, CALR and MPL genes in MPN patients, and the JAK2V617F gene process in MPN patients was found. The mutation of CALR and MPL gene mutations did not increase the rate of thrombosis in MPN patients.2. The expression of pSTAT3, TNF- a mRNA, and IL-6 mRNA in the mononuclear cells of patients with MPN suggested IL-6 related. One of the mechanisms of the disease.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R733.3

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