【摘要】：背景和目的多發(fā)性骨髓瘤(MM)是一種惡性血液系統(tǒng)腫瘤,髓外病變(EMD)是其表現(xiàn)形式之一,往往提示預(yù)后不良。EMD患者的預(yù)后有很大異質(zhì)性,其發(fā)病機(jī)制、危險(xiǎn)因素并不明確,細(xì)胞遺傳學(xué)異常是目前研究的熱點(diǎn)。MYC是重要的原癌基因,基因重排常見于高度侵襲性腫瘤,近年來發(fā)現(xiàn)其異常與MM疾病進(jìn)展相關(guān),可被Muc1、 Pyk2等基因激活,但MYC在EMD和MM預(yù)后中的意義目前仍缺乏大宗報(bào)道。本研究主要目的：(1)研究MYC異常及蛋白表達(dá)水平與EMD的相關(guān)性,探討其在MM中的預(yù)后意義。(2)比較EMD及孤立性漿細(xì)胞瘤(SP)患者的細(xì)胞遺傳學(xué)異常,探討漿細(xì)胞克隆演變?cè)贓MD發(fā)生中的作用。(3)利用骨髓瘤細(xì)胞系體外研究Pyk2和Muc1對(duì)MYC的影響,探究髓外病變中MYC激活的可能機(jī)制。方法研究納入北京協(xié)和醫(yī)院2008年1月至2015年11月初診的患者。采用病例對(duì)照分析方法收集髓外病變(EMD)和非髓外病變(nonEMD)患者,熒光原位雜交(FISH)方法研究骨髓懸液MYC異常；免疫組織化學(xué)(IHC)方法研究骨髓病理標(biāo)本中Myc、Muc1、Pyk2蛋白表達(dá)情況。選取EMD患者髓外漿細(xì)胞瘤病理標(biāo)本,以同期經(jīng)北京協(xié)和醫(yī)院病理科診斷的孤立性漿細(xì)胞瘤標(biāo)本(SP)作為對(duì)照,FISH方法研究其MYC異常,1q21擴(kuò)增、8p21缺失、RB1缺失、D13S319缺失、P53缺失、IGH重排,IHC方法研究Myc、Muc1、Pyk2蛋白表達(dá)情況。體外研究采用MM細(xì)胞系U266、RPMI8226及漿細(xì)胞白血病(PCL)細(xì)胞系NCI-H929,研究Myc抑制劑、Pyk2抑制劑和硼替佐米對(duì)細(xì)胞增殖、凋亡和侵襲性的影響。結(jié)果1.對(duì)65例nonEMD患者和42例EMD患者的初診骨髓標(biāo)本檢測(cè)MYC重排及Myc、 Muc1和Pyk2蛋白表達(dá)情況。兩組患者總生存期(OS)存在顯著差異(未達(dá)vs24月,p=0.021)。MYC重排在nonEMD組和EMD組發(fā)生率分別為20.0%和33.3%(p=0.121),在非骨旁EMD中發(fā)生率(42.3%) (p=0.029), MYC重排和1q21擴(kuò)增雙陽性在nonEMD組和EMD組發(fā)生率分別為6.2%和23.8%(p=0.025)。MYC重排陽性者中位生存期為15.4月,MYC重排陰性者中位生存期未達(dá)(p0.001)。單純1q21擴(kuò)增或8p21缺失并不顯著降低患者生存,但MYC重排合并1q21擴(kuò)增或8p21缺失中位生存期顯著縮短,分別為11.0月(p=0.001)和11.0月(p=0.010)。多因素分析發(fā)現(xiàn)MYC重排陽性為MM預(yù)后差的獨(dú)立危險(xiǎn)因素(p0.001)。免疫組化結(jié)果：新診斷MM患者骨髓Myc高表達(dá)在nonEMD組和EMD組分別為15.7%和48.2%(p0.001), Muc1高表達(dá)在nonEMD組和EMD組發(fā)生率分別為16.3%和35.2%(p=0.030)。在Muc1高表達(dá)組Myc表達(dá)水平顯著升高(34.2%vs 20.8%, p=0.010), Pyk2高表達(dá)組Myc表達(dá)水平顯著升高(29.6%vs18.0,p=0.011)。 Myc蛋白表達(dá)與基因異常并不完全吻合。2.對(duì)32例EMD及14例SP漿細(xì)胞瘤病理組織行FISH檢測(cè),EMD中MYC重排(46.7%vs14.3%,p=0.038)、1q21擴(kuò)增(65.5%vs14.3%, p=0.002)、 8p21缺失(37.9%vs0%, p=0.008)、 RBI缺失(65.5%vs14.3%, p=0.001 )、 D13S319 (58.6%vs21.4%,p=0.022)、 P53缺失(37.9%vs0%,p=0.008))、 IGH重排(48.3%vs 7.1%,p=0.015)發(fā)生率均顯著高于SP組。大部分EMD患者髓外組織與骨髓組織相比,漿細(xì)胞出現(xiàn)新的細(xì)胞遺傳學(xué)異常。Myc蛋白高表達(dá)率在EMD組高于SP組(43.3%vsl6.7%),但無顯著性差異(P=0.103)。一例MYC陽性的SP組患者最終在兩年內(nèi)進(jìn)展至活動(dòng)性骨髓瘤。3.抑制Myc可降低MM細(xì)胞的侵襲能力,抑制Pyk2可降低細(xì)胞Myc表達(dá)水平,降低細(xì)胞侵襲能力。結(jié)論EMD患者預(yù)后不良,但結(jié)局有很大異質(zhì)性。MYC重排在EMD患者中發(fā)生率高,是MM預(yù)后不良的獨(dú)立危險(xiǎn)因素。EMD細(xì)胞遺傳學(xué)異常的發(fā)生率顯著高于SP,且髓外病變具有更多的細(xì)胞遺傳學(xué)異常。Myc表達(dá)與細(xì)胞侵襲性相關(guān),Muc1和Pyk2可能通過激活Myc造成不良預(yù)后。
[Abstract]:Background and Objective Multiple myeloma (MM) is a malignant blood system tumor, and extramedullary disease (EMD) is one of its manifestations, often indicating poor prognosis. The prognosis of EMD patients is very heterogeneous, and its pathogenesis and risk factors are not clear, and the cytogenetic abnormality is the hot spot of the present study. MYC is an important proto-oncogene, and gene rearrangement is common in highly invasive tumors. In recent years, it has been found that its abnormality is related to the progression of MM disease, and can be activated by the genes such as Muco1, Pyk2, etc., but the significance of MYC in the prognosis of EMD and MM is still short of mass report. The main purpose of this study was to study the relationship between the level of MYC and the level of protein expression and EMD, and to explore its prognostic significance in MM. (2) The cytogenetic abnormality of the patients with EMD and isolated plasma cell tumor (SP) was compared, and the role of plasma cell clone evolution in the generation of EMD was discussed. (3) The possible mechanism of MYC activation in extramedullary disease was investigated by using myeloma cell line to study the effect of Py2 and Muc1 on MYC in vitro. Methods The patients who were first diagnosed between January 2008 and November 2015 were included in the study. Myc, Muc1 and Py2 protein expression in the bone marrow specimens were studied by means of a case-control analysis method in patients with extramedullary disease (EMD) and non-extramedullary disease (nonEMD) and in situ hybridization (FISH). The pathological specimens of the extramedullary plasmacytoma of the EMD patients were selected as control and the isolated plasma cell tumor specimens (SP) diagnosed by the pathology department of Peking Union and the hospital were used as control and the FISH method was used to study the MYC abnormality, 1q21 amplification, 8p21 deletion, RB1 deletion, D13S319 deletion, P53 deletion, IGH rearrangement and IHC method to study Myc. Muc1, Py2 protein expression. The effects of Myc inhibitor, Py2 inhibitor and bortezomib on cell proliferation, apoptosis and invasiveness were investigated in vitro using the MM cell line U266, the RPMI8226 and the plasma cell leukemia (PCL) cell line NCI-H929. Results 1. MYC rearrangement and the expression of Myc, Muc1 and Py2 were detected in 65 nonEMD patients and 42 patients with EMD. There was a significant difference in overall survival (OS) between the two groups (not up to vs24, p = 0.021). The incidence of MYC rearrangement in nonEMD and EMD groups was 20.0% and 33.3% (p = 0.121), respectively. The incidence of MYC rearrangements (42.3%) (p = 0.029), MYC rearrangement, and 1 q21 amplification of double-positive in nonEMD and EMD groups was 6.2% and 23.8% (p = 0.025), respectively. The median survival time of MYC rearrangement was 15.4 months. The median survival of the MYC rearrangement negative was not reached (p0.001). The simple 1q21 amplification or 8p21 deletion did not significantly reduce the survival of the patient, but the median survival of the MYC rearrangement combined with the 1q21 amplification or the 8p21 deletion was significantly shortened, respectively (p = 0.001) and 11.0 months (p = 0.010). The multi-factor analysis found that MYC rearrangement was an independent risk factor for the poor prognosis of MM (p0.001). The results showed that the high expression of Myc in bone marrow of newly diagnosed MM patients was 15.7% and 48.2% (p0.001) in nonEMD and EMD, 16.3% and 35.2% (p = 0.030) in non-EMD and EMD groups, respectively. The expression of Myc in the high-expression group of the Muc1 was significantly higher (34.2% vs. 20.8%, p = 0.010), and the expression of Myc in the high-expression group of Py2 was significantly higher (29.6% vs18.0, p = 0.011). Myc protein expression and gene abnormality did not match completely. 32 cases of EMD and 14 cases of SP plasmacytoma were detected by FISH, MYC rearrangement in EMD (46.7% vs14.3%, p = 0.038), 1q21 amplification (65.5% vs14.3%, p = 0.002), 8p21 deletion (37.9% vs0%, p = 0.008), RBI deletion (65.5% vs14.3%, p = 0.001), D13S319 (58.6% vs23.4%, p = 0.022), P53 deletion (37.9% vs0%, p = 0.008), IGH rearrangement (48.3% vs. 7.1%, The p = 0.015) incidence was significantly higher in the SP group. In most of the EMD patients, there were new cytogenetic abnormalities in plasma cells compared to the bone marrow tissue. The high expression rate of Myc protein was higher in the EMD group than in the SP group (43.3% vsl6.7%), but there was no significant difference (P = 0.103). One case of a MYC-positive SP group eventually progressed to active myeloma within two years. Inhibiting Myc can reduce the invasion ability of MM cells, and inhibit Pyk2 to lower the expression level of the cell Myc and reduce the cell invasion ability. Conclusion The prognosis of EMD is poor, but the outcome is very heterogeneous. The high incidence of MYC rearrangement in patients with EMD is an independent risk factor for the poor prognosis of MM. The incidence of cytogenetic abnormalities was significantly higher in the EMD than in the SP, and more cytogenetic abnormalities were found in the extramedullary lesions. Myc expression is associated with cell invasiveness, and Muc1 and Pyk2 may cause poor prognosis by activating Myc.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【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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