独立生长因子Gfi1基因在骨髓增殖性疾病中的作用与机理研究
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摘要
目的：探索独立生长因子Gfi1在髓系细胞增殖和凋亡中的作用,为骨髓增殖性疾病(MPD)的分子学诊断和治疗提供理论依据。
方法：(1)通过绿色荧光蛋白GFP慢病毒载体包装系统把目的基因Gfi1和对照组空质粒Plox稳定转染入依赖白介素3(IL-3)生长的小鼠32D粒-单祖细胞细胞株中,无菌流式分选出32D/Gif1和32D/Plox细胞株。(2)通过细胞生长、集落生长和细胞周期的变化等实验来分析32D/Gfi1和32D/Plox细胞株增殖的变化；(3)IL-3撤退实验后,通过流式细胞术、细胞染色(碘化丙啶和Hoechst 33258)、蛋白免疫印迹(WB)等技术来分析32D/Gfi1和32D/Plox细胞株凋亡的变化。
结果：(1)稳定转染Gfi1的细胞株(32D/Gfi1)和集落与对照组空质粒Plox的细胞株(32D/Plox)和集落的增殖差异明显,32D/Gfi1细胞增殖速度和集落形成率均明显高于32D/Plox细胞株；过表达Gfi1可以促使32D细胞由G0/G1期进入S期,加速细胞周期进程。(2)IL-3撤退48小时后,流式细胞术分析结果显示：32D/Plox细胞出现的凋亡显著多于32D/Gfi1细胞(分别为89.72%和34.52%,P<0.01)；Western blot结果显示：相对于32D/Plox组,32D/Gfi1组的凋亡促进因子Bax和细胞周期依赖性激酶抑制基因(CDKN2A)编码的两种周期抑制蛋白(p16INK4a和p14ARF,以下简称P14,P16)的水平明显下调。
结论：在小鼠32D粒-单核祖细胞株中,Gfi1能够促进细胞增殖、增加集落形成率和加速细胞周期进程；Gfi1能够抑制与细胞周期和凋亡相关的Bax、p16INK4a和p14ARF的表达,从而减少因IL-3撤退引起的32D细胞凋亡。
目的：建立小鼠骨髓增殖性疾病(Myeloproliferative disorders, MPD)小鼠模型,探讨独立生长因子(growth factor independence 1, Gfi1)在MPD发病中的作用与机理。
方法：选择DBA小鼠,实验动物按移植物不同随机分为3组,A组10只,B组20只,C组4只。移植当天将受鼠置于无菌笼内接受直线加速器亚致死剂量4.0Gy,进行照射,每只小鼠照射后4h内由尾静脉输注入移植物,每只受鼠输入细胞体积为200μl；每只小鼠输入的细胞数1.8×106个；A组输入32D/plox细胞,B组输入32D/Gfi1细胞,C组只做照射,不输细胞,留正常未处理小鼠做血象检测的对照。检测血象、检查嵌合体植入、观察肝、脾、骨的病理改变；Western-blot检测32D/plox小鼠和32D/Gfi1组小鼠Gfi1与JAK2的表达变化。
结果：实时定量PCR检测Gfil mRNA在32D/plox小鼠和32D/Gfi1小鼠中的表达,后者显著增高,提示移植物成活；通过Y染色体上的sry基因的PCR扩增检测阳性也说明移植32D/Gfi1细胞成功。血象在30d、60d可检测到32D/Gfi1组小鼠的WBC、RBC、Plt显著增加,明显高于32D/plox小鼠和正常小鼠的血象,且差异有统计学意义(P<0.05),且以后持续保持在较高的血象水平,符合MPD的血象表现。32D/Gfi1小鼠肝脏、脾脏、骨髓的病理改变均符合MPD改变；32D/Gfi1组小鼠表达的Gfi1的mRNA、蛋白及JAK2的mRNA、蛋白比空白载体32D/plox组明显增强。
结论：建立了稳定的MPD小鼠动物模型,过表达Gfi1通过增加JAK2的表达促使MPD的发生。
目的：探讨骨髓增殖性疾病(myeloproliferative disorders, MPD)患者骨髓中独立生长因子(growth factor independence 1,Gfi1)的表达及其与临床预后的关系。方法：选择华中科技大学同济医学院附属同济医院医院确诊的74例MPD患者为研究对象,其中真性红细胞增多(polycythaemiavera, PV)23例、原发性血小板增多症(essential throm bocythaemia, ET)49例,特发性骨髓纤维化(idiopathic myelofibrosis,IMF)2例。应用逆转录-聚合酶链反应技术扩增Gfi1引物,琼脂糖凝胶电泳结果,分析各组MPD患者Gfi1阳性表达与MPD临床预后的关系。
结果：74例MPD患者中52例检出Gfi1阳性表达,分别为PV患者78.26%(18/23)阳性表达,ET患者67.35%(33/49)阳性表达,IMF患者50%(1/2)阳性表达。Gfi1水平增高影响患者的预后,Gfi1阳性表达者,预后较差。
结论：Gfi1可作为判断MPD预后的重要指标。
Research aims:The growth factor independent-1 (Gfi1) is a transcriptional repressor with essential roles in lymphopoiesis, myelopoiesis, and hematopoietic stem cell development. Here we will further investigate the functions of Gfil in myeloid proliferation and apoptosis.
Methods:We cloned the full-length sequences of human's Gfi-1 by using gene cloning and recombinant molecular biology, and constructed pLOX-Gfi-1. We introduced Gfi1 cDNA into the interleukin-3 (IL-3) dependent mouse myelomonoblastic 32D progenitor cells. By observing the colony-forming units, performing cell growth curve and cell cycle distribution analysis, we studied the proliferative ability of Gfi1. By using Propidium Iodide and Hoechst staining, apoptosis assays with flow cytometry and western blot assays, we investigated the proliferation and apoptosis in 32D/Gfil cells and 32D/plox cells after withdrawal of IL-3.
Results:The plating efficiency of 32D/Gfi1 cells was much higher than that of control cells (32D/Plox) in colony formation assay. Overexpression of Gfi-1 promotes the entry of 32D cells from G0/G1 resting state into the S phase, thus results in enhanced proliferation through accelerated cell cycle progression. More importantly, overexpression of Gfi1 significantly reduced cell death initiated by IL-3 withdrawal. After 48 hours deprivation, more 32D/Plox cells showed morphology of apoptosis compared to 32D/Gfil cells (89.72% vs 34.52%, p<0.01). In accordance with the phenomenon, the protein levels of the proapoptotic regulator Bax and two CDKN2A encoding proteins p16INK4A and p14ARF are down-regulated by Gfi-1 overexpresssion.
Conclusion:Gfi-1 is believed to promote proliferation and inhibit apoptosis through its simultaneous acceleration of cell cycle and repression of apoptosis-related factors.
Research aims:To Establish mice model of myeloproliferative disorders (MPD) and study the effect and mechanism of growth factor independence 1 on myeloproliferative disease in mice.
Methods:We select DBA mice as the test animals. According to the graft cells, the mice were randomly divided into 3 groups, group A was n=10, group B was n=20, and group C was n=4. Recipient mice were placed within a sterile cage received sublethal doses of 4.0Gy Linear accelerator radiation. The graft was input into the tail vein in 4 hours after irradiation. Group A was input 32D/plox cells, group B was input 32D/Gfi1, and group C only exposed to the rays, but not accepted graft. The recipients were observed for the features of MPD, such as anemia, anorexia, etc. The evidence of successful transplantation was shown by real-time quantitative PCR detection of Gfi1 mRNA in the recipient mice, and the amplification of mice Y chromosome specific DNA by PCR from the recipient bone marrow. HE stain histology was also performed for livers, spleen and bones in recipients at different time points. Quantitative RT-PCR and western blot were used to tracking the mRNA and protein expression of Gfi1 and JAK2.
Results:(1) Typical features were seen in the mice MPD models, such as Increased blood count. anorexia, less activity, etc. (2) Gfi1 mRNA was significantly higher in group B than in group A. Also, PCR assays confirmed that complete chimerism was successfully established in recipient mice. Detecting blood count in the 30d,60d, WBC, RBC and Plt were significant increased in group B mice than in group A, and the difference was statistically significant (P<0.05). We found the pathological changes of liver, spleenand bone marrow were consistent with the changes in MPD. The mRNA and protein expression of Gfi1 and JAK2 in group B mice were significantly enhanced than that in the group A mice.
Conclusion:Stable and reliable MPD model was established. Overexpression of Gfi1 led to the occurrence of MPD in mice by promoting the expression of JAK2.
Objective:To examine the expression Gfi1 in patients with myeloproliferative disorders (MPD) and its relationship with clinic prognostic significance of MPD.
Methods:Seventy-four MPD patients (who had been diagnosed in Tongji Hospital) were included in our study. The patients included 23 with polycythaemiavera (PV),49 with essential thrombocythaemia (ET) and 2 with idiopathicmyelofibrosis (IMF). Gfi1 was detected by reverse transcription polymerase chain reaction (RT-PCR). Agarose gel electrophoresis is used to separate DNA-sequencing. The correlation of Gfi1 with clinical prognosis of MPD was analyzed by Chi-square test.
Results:Gfi1 positive was detected in 52 of the 74 MPD patients, including 18 (18/23, 78.26%) with PV,33 (33/49,67.35%) with ET, and 1 (1/2,50%) with IMF. Positive expression of Gfi1 affects the prognosis of the MPD patients. Patients with positive Gfi1 were significantly different from healthy volunteers, indicating poor prognosis.
Conclusion:Gfi1 could be used as an important prognostic indicator in MPD.
方法：(1)通过绿色荧光蛋白GFP慢病毒载体包装系统把目的基因Gfi1和对照组空质粒Plox稳定转染入依赖白介素3(IL-3)生长的小鼠32D粒-单祖细胞细胞株中,无菌流式分选出32D/Gif1和32D/Plox细胞株。(2)通过细胞生长、集落生长和细胞周期的变化等实验来分析32D/Gfi1和32D/Plox细胞株增殖的变化；(3)IL-3撤退实验后,通过流式细胞术、细胞染色(碘化丙啶和Hoechst 33258)、蛋白免疫印迹(WB)等技术来分析32D/Gfi1和32D/Plox细胞株凋亡的变化。
结果：(1)稳定转染Gfi1的细胞株(32D/Gfi1)和集落与对照组空质粒Plox的细胞株(32D/Plox)和集落的增殖差异明显,32D/Gfi1细胞增殖速度和集落形成率均明显高于32D/Plox细胞株；过表达Gfi1可以促使32D细胞由G0/G1期进入S期,加速细胞周期进程。(2)IL-3撤退48小时后,流式细胞术分析结果显示：32D/Plox细胞出现的凋亡显著多于32D/Gfi1细胞(分别为89.72%和34.52%,P<0.01)；Western blot结果显示：相对于32D/Plox组,32D/Gfi1组的凋亡促进因子Bax和细胞周期依赖性激酶抑制基因(CDKN2A)编码的两种周期抑制蛋白(p16INK4a和p14ARF,以下简称P14,P16)的水平明显下调。
结论：在小鼠32D粒-单核祖细胞株中,Gfi1能够促进细胞增殖、增加集落形成率和加速细胞周期进程；Gfi1能够抑制与细胞周期和凋亡相关的Bax、p16INK4a和p14ARF的表达,从而减少因IL-3撤退引起的32D细胞凋亡。
目的：建立小鼠骨髓增殖性疾病(Myeloproliferative disorders, MPD)小鼠模型,探讨独立生长因子(growth factor independence 1, Gfi1)在MPD发病中的作用与机理。
方法：选择DBA小鼠,实验动物按移植物不同随机分为3组,A组10只,B组20只,C组4只。移植当天将受鼠置于无菌笼内接受直线加速器亚致死剂量4.0Gy,进行照射,每只小鼠照射后4h内由尾静脉输注入移植物,每只受鼠输入细胞体积为200μl；每只小鼠输入的细胞数1.8×106个；A组输入32D/plox细胞,B组输入32D/Gfi1细胞,C组只做照射,不输细胞,留正常未处理小鼠做血象检测的对照。检测血象、检查嵌合体植入、观察肝、脾、骨的病理改变；Western-blot检测32D/plox小鼠和32D/Gfi1组小鼠Gfi1与JAK2的表达变化。
结果：实时定量PCR检测Gfil mRNA在32D/plox小鼠和32D/Gfi1小鼠中的表达,后者显著增高,提示移植物成活；通过Y染色体上的sry基因的PCR扩增检测阳性也说明移植32D/Gfi1细胞成功。血象在30d、60d可检测到32D/Gfi1组小鼠的WBC、RBC、Plt显著增加,明显高于32D/plox小鼠和正常小鼠的血象,且差异有统计学意义(P<0.05),且以后持续保持在较高的血象水平,符合MPD的血象表现。32D/Gfi1小鼠肝脏、脾脏、骨髓的病理改变均符合MPD改变；32D/Gfi1组小鼠表达的Gfi1的mRNA、蛋白及JAK2的mRNA、蛋白比空白载体32D/plox组明显增强。
结论：建立了稳定的MPD小鼠动物模型,过表达Gfi1通过增加JAK2的表达促使MPD的发生。
目的：探讨骨髓增殖性疾病(myeloproliferative disorders, MPD)患者骨髓中独立生长因子(growth factor independence 1,Gfi1)的表达及其与临床预后的关系。方法：选择华中科技大学同济医学院附属同济医院医院确诊的74例MPD患者为研究对象,其中真性红细胞增多(polycythaemiavera, PV)23例、原发性血小板增多症(essential throm bocythaemia, ET)49例,特发性骨髓纤维化(idiopathic myelofibrosis,IMF)2例。应用逆转录-聚合酶链反应技术扩增Gfi1引物,琼脂糖凝胶电泳结果,分析各组MPD患者Gfi1阳性表达与MPD临床预后的关系。
结果：74例MPD患者中52例检出Gfi1阳性表达,分别为PV患者78.26%(18/23)阳性表达,ET患者67.35%(33/49)阳性表达,IMF患者50%(1/2)阳性表达。Gfi1水平增高影响患者的预后,Gfi1阳性表达者,预后较差。
结论：Gfi1可作为判断MPD预后的重要指标。
Research aims:The growth factor independent-1 (Gfi1) is a transcriptional repressor with essential roles in lymphopoiesis, myelopoiesis, and hematopoietic stem cell development. Here we will further investigate the functions of Gfil in myeloid proliferation and apoptosis.
Methods:We cloned the full-length sequences of human's Gfi-1 by using gene cloning and recombinant molecular biology, and constructed pLOX-Gfi-1. We introduced Gfi1 cDNA into the interleukin-3 (IL-3) dependent mouse myelomonoblastic 32D progenitor cells. By observing the colony-forming units, performing cell growth curve and cell cycle distribution analysis, we studied the proliferative ability of Gfi1. By using Propidium Iodide and Hoechst staining, apoptosis assays with flow cytometry and western blot assays, we investigated the proliferation and apoptosis in 32D/Gfil cells and 32D/plox cells after withdrawal of IL-3.
Results:The plating efficiency of 32D/Gfi1 cells was much higher than that of control cells (32D/Plox) in colony formation assay. Overexpression of Gfi-1 promotes the entry of 32D cells from G0/G1 resting state into the S phase, thus results in enhanced proliferation through accelerated cell cycle progression. More importantly, overexpression of Gfi1 significantly reduced cell death initiated by IL-3 withdrawal. After 48 hours deprivation, more 32D/Plox cells showed morphology of apoptosis compared to 32D/Gfil cells (89.72% vs 34.52%, p<0.01). In accordance with the phenomenon, the protein levels of the proapoptotic regulator Bax and two CDKN2A encoding proteins p16INK4A and p14ARF are down-regulated by Gfi-1 overexpresssion.
Conclusion:Gfi-1 is believed to promote proliferation and inhibit apoptosis through its simultaneous acceleration of cell cycle and repression of apoptosis-related factors.
Research aims:To Establish mice model of myeloproliferative disorders (MPD) and study the effect and mechanism of growth factor independence 1 on myeloproliferative disease in mice.
Methods:We select DBA mice as the test animals. According to the graft cells, the mice were randomly divided into 3 groups, group A was n=10, group B was n=20, and group C was n=4. Recipient mice were placed within a sterile cage received sublethal doses of 4.0Gy Linear accelerator radiation. The graft was input into the tail vein in 4 hours after irradiation. Group A was input 32D/plox cells, group B was input 32D/Gfi1, and group C only exposed to the rays, but not accepted graft. The recipients were observed for the features of MPD, such as anemia, anorexia, etc. The evidence of successful transplantation was shown by real-time quantitative PCR detection of Gfi1 mRNA in the recipient mice, and the amplification of mice Y chromosome specific DNA by PCR from the recipient bone marrow. HE stain histology was also performed for livers, spleen and bones in recipients at different time points. Quantitative RT-PCR and western blot were used to tracking the mRNA and protein expression of Gfi1 and JAK2.
Results:(1) Typical features were seen in the mice MPD models, such as Increased blood count. anorexia, less activity, etc. (2) Gfi1 mRNA was significantly higher in group B than in group A. Also, PCR assays confirmed that complete chimerism was successfully established in recipient mice. Detecting blood count in the 30d,60d, WBC, RBC and Plt were significant increased in group B mice than in group A, and the difference was statistically significant (P<0.05). We found the pathological changes of liver, spleenand bone marrow were consistent with the changes in MPD. The mRNA and protein expression of Gfi1 and JAK2 in group B mice were significantly enhanced than that in the group A mice.
Conclusion:Stable and reliable MPD model was established. Overexpression of Gfi1 led to the occurrence of MPD in mice by promoting the expression of JAK2.
Objective:To examine the expression Gfi1 in patients with myeloproliferative disorders (MPD) and its relationship with clinic prognostic significance of MPD.
Methods:Seventy-four MPD patients (who had been diagnosed in Tongji Hospital) were included in our study. The patients included 23 with polycythaemiavera (PV),49 with essential thrombocythaemia (ET) and 2 with idiopathicmyelofibrosis (IMF). Gfi1 was detected by reverse transcription polymerase chain reaction (RT-PCR). Agarose gel electrophoresis is used to separate DNA-sequencing. The correlation of Gfi1 with clinical prognosis of MPD was analyzed by Chi-square test.
Results:Gfi1 positive was detected in 52 of the 74 MPD patients, including 18 (18/23, 78.26%) with PV,33 (33/49,67.35%) with ET, and 1 (1/2,50%) with IMF. Positive expression of Gfi1 affects the prognosis of the MPD patients. Patients with positive Gfi1 were significantly different from healthy volunteers, indicating poor prognosis.
Conclusion:Gfi1 could be used as an important prognostic indicator in MPD.
引文
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