转录因子GATA2及辅转录因子CREB结合蛋白在正常核型急性髓系白血病中的表达调控及意义
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摘要
目的：急性髓系白血病（acute myeloid leukemia，AML）是一组异质性很强的恶性克隆增殖性肿瘤，随着分子生物学技术的普及，近几年在正常核型急性髓细胞白血病(cytogenetically normal acute myeloid leukemia，CN-AML)患者中发现一些基因突变和基因异常表达(包括FLT3突变、NPM1和CEBPA等)，并显著影响临床预后。分子标志的发现和研究为CN-AML的诊断、治疗、预后提供了重要依据，有重要的临床应用价值。
GATA2为转录因子家族成员，在造血干/祖细胞的增殖分化中起着重要作用。GATA2在血细胞生成过程中的生物学功能以及其表达的平衡性可能与白血病的发生有关。在分化过程中各种不同的造血细胞谱系内GATA-2的表达逐渐降低，因而过表达及活化的GATA2可抑制造血细胞正常分化的能力，同时可促进白血病的转化。CREB结合蛋白（CBP）是GATA-2的辅激活因子，CBP通过与基本转录因子和一些序列专一的转录激活因子相互作用,为二者提供了一个相互作用的“桥”。不论是在体内还是在体外CBP均能与GATA-2结合，并能够以剂量依赖的方式提高GATA-2转录激活的活性。同时CBP蛋白与GATA-2选择性结合时可维持造血细胞的非分化状态,故对此状态下造血祖细胞的发育机制的研究将有助于我们控制白血病和与造血祖细胞分化异常相关的疾病。本实验旨在探讨GATA-2基因及CBP的表达与白血病的转归及二者共同作用与CN-AML发病的关系。同时从细胞发育、增殖、分化等方面多角度深入研究GATA-2及CBP在CN-AML发生发展中的表达特性，从中逐步明确其发生机理，为CN-AML的治疗提供新的思路并为提高CN-AML的治愈率及长期无病生存率打下基础。
方法：
1收集2011.4-2012.1部分在河北医科大学第二医院血液内科住院及门诊的AML患者骨髓液标本共87例，将其分为初治组（34例）、复发组（8例）、缓解组（45例），其中初治组及复发组经染色体检测均为正常核型；并设11例非恶性血液病患者为对照组。
2使用淋巴细胞分离液提取骨髓液中单个核细胞。
3应用半定量逆转录-聚合酶链反应（semi-quantity reversetranscription-polymerase chain reaction, RT-PCR）检测各组GATA2、CBPmRNA的表达水平。
4统计学处理；
结果：
1GATA2mRNA在各组中的表达
1.1GATA2mRNA在34例初治CN-AML患者中33例表达阳性，基因相对表达水平（GATA2-actin）为1.299（1.496），阳性率为97.1%；在8例复发CN-AML患者中8例表达阳性，相对表达水平为1.367（1.734），阳性率为100%。初治组和复发组表达水平与表达率无差别，但初治组表达水平明显高于对照组（11例非恶性血液病患者中6例表达阳性，阳性率为54.5%，平均水平为0.592（0.916）），结果具有显著性差异（P<0.05）。GATA2mRNA在45例缓解组中有40例表达阳性，平均表达水平为0.412（1.079），阳性率为88.9%，与正常对照组比较无统计学差异（P>0.05），但表达水平和阳性率均低于初治CN-AML组，且差别有显著性（P<0.05）。
1.2GATA2表达与治疗缓解率的关系：在34名初治CN-AML患者中，GATA2表达阳性者33例，阳性表达率为97.1%。其中，GATA2高表达组（GATA2表达水平≥1.599为高表达组）中有12例获得缓解，缓解率为92.31%；GATA2低表达组（GATA2表达水平＜1.599为低表达组）中有15例获得缓解，缓解率为75%。GATA2高表达组缓解率与GATA2低表达组之间治疗缓解率差别无统计学意义（P>0.05）。
2CBP mRNA在各组中的表达
2.1CBP mRNA在34例初治CN-AML患者中33例表达阳性，阳性率为97.1%，表达水平为1.070（1.661）；在8例复发CN-AML患者中8例表达阳性，阳性率为100%，表达水平为1.546（0.347）；CBP mRNA在45例缓解患者中42例表达阳性，阳性率为93.3%，表达水平为0.451（0.908）；在11例对照组中11例表达阳性，阳性率为100%，表达水平为0.591(0.358)。经统计学分析，除初治-复发组、强化-正常组外，CBP mRNA在其余各组中表达水平均有显著差异（P<0.05）。
2.2CBP表达与治疗缓解率及预后的关系：在34名初治CN-AML患者中，CBP表达阳性者33例，阳性表达率为97.1%。其中，CBP高表达组（CBP表达水平≥1.427为高表达组）缓解率为83.33%，低表达组（CBP表达水平＜1.427为低表达组）缓解率为80.95%，二者治疗缓解率无统计学差别（P>0.05）。
3在CN-AML初治组中，GATA2mRNA和CBP mRNA共表达率为94.12%。
4初治组中GATA2、CBPmRNA的表达量与白细胞计数、血红蛋白、血小板计数及原幼细胞数之间均无相关性（P>0.05）。对进行了CD34检测的18例初治CN-AML患者的GATA2、CBP mRNA表达水平和CD34阳性细胞数分别进行相关分析，发现两者也无明显相关性（P>0.05）。
5治疗前后GATA2、CBP mRNA表达水平的变化：对初治组16例CN-AML患者进行追踪观察，于化疗前、缓解后检测其骨髓单个核细胞的GATA2、CBP mRNA的表达情况。结果显示治疗前GATA2mRNA表达水平为1.699（1.243），缓解后GATA2mRNA的表达水平为0.212（1.011），较治疗前明显降低，差别有统计学意义（P<0.05）。治疗前CBP mRNA表达水平为1.437（2.160），缓解后CBP mRNA的表达水平0.323（0.919）明显降低，差别有统计学意义（P<0.05）。
结论：
1在CN-AML患者初治组及复发组中，GATA2mRNA表达异常增高，而在缓解组其表达水平较低，与正常组无差别。CBP mRNA在初治组、复发组表达水平明显高于缓解组、正常组，差别有意义。而且两基因初治组、复发组与正常组之间的表达率有明显差别。提示，GATA2、CBP参与了急性白血病发病过程，为AML分层治疗提供理论依据。
2GATA2及CBP mRNA表达水平的高低并不影响CR率。根据诱导缓解治疗过程中对两基因的表达水平进行监测，发现两基因在完全缓解后表达水平均明显降低，与治疗前相比差别具有显著性。本研究说明CN-AML中对GATA2和CBP的动态监测可作为评价治疗效果和预测复发的指标。
3初治组CN-AML中GATA2和CBP的表达量之间存在秩相关。目前我们可以认为GATA2和CBP在白血病的发病过程中共同发挥作用。CBP作为GATA2的辅激活因子应用于急性白血病中，并可联合GATA2共同预测CN-AML预后。
Objective： Acute myeloid leukemia (AML) is a tumor of highlymalignant cloning proliferation. In recent years， with the popularity ofmolecular biology techniques， the number of gene mutations and abnormalgene expression (including FLT3mutations, NPM1and CEBPA) were foundin patients with normal karyotype acute myeloid leukemia (CN-AML)., andsignificantly affect the clinical outcome. The discovery and study of molecularmarkers provides an important basis for the CN-AML diagnosis, treatment andprognosis.
The biological functions of GATA2in hematopoietis and the importanceof its balanced expression led to the suggestion that it might be involved inleukemogenesis. Since GATA2levels decreased with differentiation in each ofthe various hematopoietic sub-lineages, this pattern might reflect the ability ofoverexpressed or activated GATA2to suppress normal differentiation andpromote leukemic transformation. CREB-binding proteins (CBP) as atranscriptional coactivator of GATA-2。CBP is a transcription adaptor by directbridging between basic transcription factors and several sequence-specifictranscriptional activator. Both in vivo or in vitro CBP can combination withGATA-2, and be able to improve the activity of GATA-2transcriptionalactivation in a dose-dependent manner. CBP protein expression of GATA-2selective binding to maintain the undifferentiated state of hematopoietic cells,it is this state of hematopoietic progenitor cells and development mechanismwill help us to control the leukemia and abnormal differentiation ofhematopoietic progenitor cells diseases. The study was to investigate therelationship between the expression of GATA-2/CBP and the development ofacute leukemia, then to investigate whether there was some relationship between the coexpression of GATA-2/CBP and the pathogenesis of acuteleukemia. Multi-angle and other aspects of cell development, proliferation,differentiation-depth study of the expression characteristics of the GATA-2and CBP in the development of acute leukemia, which gradually clear itsmechanism, to provide new ideas for the treatment of CN-AML and toimprove the cure of leukemiarate and long-term disease-free survival lay thefoundation。
Methods:1Collect bone marrow fluid samples of2011.4-2012.1part inthe Second Hospital of Hebei Medical University, inpatient and outpatient fora total of87cases of AML patients(including34cases of untreated CN-AMLpatients,45cases of complete remission patients,8cases of relapse CN-AMLpatients), and11cases of normal group (patients with non-hematologicmalignancies).
2Using the lymphocyte separation medium separation of bone marrowmononuclear cells;
3Semi-quantitative reverse transcription-polymerase chain reaction（RT-PCR）to detect GATA2and CBP mRNA levels of each group;
4Statistically
Results:1The expression level of GATA2mRNA in each group
1.1The expression of GATA2mRNA in de novo CN-AML patients(mean1.299（1.469）,positive rate97.1%) and in relapse (RP) CN-AMLpatients (mean1.367（1.734）,positive rate100%). There was no differencebetween de novo and RP group。But de novo group were significantly higherthan NC (mean0.592（0.916）, positive rate54.5%)(P <0.05). The expressionof GATA2mRNA in CR group （mean0.412(1.079), positive rate88.9%）were lower than that in de novo CN-AML patients (P<0.05). But there was nodifference between CR group and NC group(P>0.05)。
1.2The de novo CN-AML patients were divided into GATA2highexpression group and GATA2low expression group. The CR rate was92.31%in GATA2high expression group, The CR rate was75%in GATA2lowexpression group, there was no difference between the GATA2high expression group and GATA2low expression group (P>0.05).
2The expression level of CBP mRNA in each group
2.1The mean expression of CBP mRNA in de novo CN-AML patientswas1.070（1.661）, the positive rate was97.1%（33/34）. In the RP-patients,the mean expression was1.546（0.347）, the positive rate was100%（8/8）. Inthe CR-patients, the mean expression was0.451（0.908）, the positive rate was93.3%（42/45）. In the NC group, they were0.591（0.358） and100%（11/11）separately. In addition to the de novo group and the RP group, the CR groupand the NC group, CBP mRNA expression level in the rest of each group inthe AL have significantly difference.
2.2The de novo CN-AML patients were divided into CBP highexpression group and CBP low expression group. The CR rate was83.33%inCBP high expression group, and there was no difference between the CBPhigh expression group and the CBP low expression group (CR rate80.95%)(P>0.05).
3There were94.12%de novo CN-AML patients measured to expressboth GATA2and CBP mRNA.
4There was no correlated between GATA2, CBP expression level andthe white blood cell count, hemoglobin, platelet count and the original numberof immature cells in the de novo group (P>0.05). Detected18CN-AMLpatients, GATA2and CBP mRNA expression level and CD34+cell countWere related to analysis, we find that there is no significant correlation (P>0.05)。
5The expression level of GATA2and CBP in the de novo group andCR group
Tracking observation the16patients with CN-AML, detected theGATA2and CBP expression level of bone marrow mononuclear cells inthe de novo group and CR group. The results showed that GATA2expressionlevels in the de novo group is1.699（1.243）, Significantly lower than the denovo group, the difference was statistically significant (P <0.05). CBPexpression levels in the de novo group is1.437（2.160）, To ease after the CBP expression level is0.323(0.919)，was significantly lower than beforetreatment, the difference was statistically significant (P <0.05)。
Conclusions:
1In de novo and relapsed CN-AML patients, the expression of GATA2mRNA abnormally increases; however，the expression is lower in completeremission group, there is no difference compared with normal group. Theexpression of CBP mRNA in de novo and relapsed patients are higher than inthe normal group and remission patients, the difference between the groupsare statistically significant. In summary, GATA2and CBP may play a moreimportant role， and provide a theoretical basis for the AML stratifiedtreatment.
2The expression level of GATA2and CBP does not affect the CRrate.Compared with the expression before chemotherapy, the expression oftwo genes obviously decrease after complete remission. Dynamic monitoringGATA2and CBP mRNA can be used as indicators to evaluate the therapeuticeffect and predict recurrence.
3The expression level of GATA2and CBP mRNA in de novo CN-AMLpatients is correlation. At present, we can assume that GATA2and CBPjointly play a role in the pathogenesis of leukemia. CBP，as a new molecularmarker used in acute leukemia, can be joint GATA2to predict the prognosisof CN-AML.
GATA2为转录因子家族成员，在造血干/祖细胞的增殖分化中起着重要作用。GATA2在血细胞生成过程中的生物学功能以及其表达的平衡性可能与白血病的发生有关。在分化过程中各种不同的造血细胞谱系内GATA-2的表达逐渐降低，因而过表达及活化的GATA2可抑制造血细胞正常分化的能力，同时可促进白血病的转化。CREB结合蛋白（CBP）是GATA-2的辅激活因子，CBP通过与基本转录因子和一些序列专一的转录激活因子相互作用,为二者提供了一个相互作用的“桥”。不论是在体内还是在体外CBP均能与GATA-2结合，并能够以剂量依赖的方式提高GATA-2转录激活的活性。同时CBP蛋白与GATA-2选择性结合时可维持造血细胞的非分化状态,故对此状态下造血祖细胞的发育机制的研究将有助于我们控制白血病和与造血祖细胞分化异常相关的疾病。本实验旨在探讨GATA-2基因及CBP的表达与白血病的转归及二者共同作用与CN-AML发病的关系。同时从细胞发育、增殖、分化等方面多角度深入研究GATA-2及CBP在CN-AML发生发展中的表达特性，从中逐步明确其发生机理，为CN-AML的治疗提供新的思路并为提高CN-AML的治愈率及长期无病生存率打下基础。
方法：
1收集2011.4-2012.1部分在河北医科大学第二医院血液内科住院及门诊的AML患者骨髓液标本共87例，将其分为初治组（34例）、复发组（8例）、缓解组（45例），其中初治组及复发组经染色体检测均为正常核型；并设11例非恶性血液病患者为对照组。
2使用淋巴细胞分离液提取骨髓液中单个核细胞。
3应用半定量逆转录-聚合酶链反应（semi-quantity reversetranscription-polymerase chain reaction, RT-PCR）检测各组GATA2、CBPmRNA的表达水平。
4统计学处理；
结果：
1GATA2mRNA在各组中的表达
1.1GATA2mRNA在34例初治CN-AML患者中33例表达阳性，基因相对表达水平（GATA2-actin）为1.299（1.496），阳性率为97.1%；在8例复发CN-AML患者中8例表达阳性，相对表达水平为1.367（1.734），阳性率为100%。初治组和复发组表达水平与表达率无差别，但初治组表达水平明显高于对照组（11例非恶性血液病患者中6例表达阳性，阳性率为54.5%，平均水平为0.592（0.916）），结果具有显著性差异（P<0.05）。GATA2mRNA在45例缓解组中有40例表达阳性，平均表达水平为0.412（1.079），阳性率为88.9%，与正常对照组比较无统计学差异（P>0.05），但表达水平和阳性率均低于初治CN-AML组，且差别有显著性（P<0.05）。
1.2GATA2表达与治疗缓解率的关系：在34名初治CN-AML患者中，GATA2表达阳性者33例，阳性表达率为97.1%。其中，GATA2高表达组（GATA2表达水平≥1.599为高表达组）中有12例获得缓解，缓解率为92.31%；GATA2低表达组（GATA2表达水平＜1.599为低表达组）中有15例获得缓解，缓解率为75%。GATA2高表达组缓解率与GATA2低表达组之间治疗缓解率差别无统计学意义（P>0.05）。
2CBP mRNA在各组中的表达
2.1CBP mRNA在34例初治CN-AML患者中33例表达阳性，阳性率为97.1%，表达水平为1.070（1.661）；在8例复发CN-AML患者中8例表达阳性，阳性率为100%，表达水平为1.546（0.347）；CBP mRNA在45例缓解患者中42例表达阳性，阳性率为93.3%，表达水平为0.451（0.908）；在11例对照组中11例表达阳性，阳性率为100%，表达水平为0.591(0.358)。经统计学分析，除初治-复发组、强化-正常组外，CBP mRNA在其余各组中表达水平均有显著差异（P<0.05）。
2.2CBP表达与治疗缓解率及预后的关系：在34名初治CN-AML患者中，CBP表达阳性者33例，阳性表达率为97.1%。其中，CBP高表达组（CBP表达水平≥1.427为高表达组）缓解率为83.33%，低表达组（CBP表达水平＜1.427为低表达组）缓解率为80.95%，二者治疗缓解率无统计学差别（P>0.05）。
3在CN-AML初治组中，GATA2mRNA和CBP mRNA共表达率为94.12%。
4初治组中GATA2、CBPmRNA的表达量与白细胞计数、血红蛋白、血小板计数及原幼细胞数之间均无相关性（P>0.05）。对进行了CD34检测的18例初治CN-AML患者的GATA2、CBP mRNA表达水平和CD34阳性细胞数分别进行相关分析，发现两者也无明显相关性（P>0.05）。
5治疗前后GATA2、CBP mRNA表达水平的变化：对初治组16例CN-AML患者进行追踪观察，于化疗前、缓解后检测其骨髓单个核细胞的GATA2、CBP mRNA的表达情况。结果显示治疗前GATA2mRNA表达水平为1.699（1.243），缓解后GATA2mRNA的表达水平为0.212（1.011），较治疗前明显降低，差别有统计学意义（P<0.05）。治疗前CBP mRNA表达水平为1.437（2.160），缓解后CBP mRNA的表达水平0.323（0.919）明显降低，差别有统计学意义（P<0.05）。
结论：
1在CN-AML患者初治组及复发组中，GATA2mRNA表达异常增高，而在缓解组其表达水平较低，与正常组无差别。CBP mRNA在初治组、复发组表达水平明显高于缓解组、正常组，差别有意义。而且两基因初治组、复发组与正常组之间的表达率有明显差别。提示，GATA2、CBP参与了急性白血病发病过程，为AML分层治疗提供理论依据。
2GATA2及CBP mRNA表达水平的高低并不影响CR率。根据诱导缓解治疗过程中对两基因的表达水平进行监测，发现两基因在完全缓解后表达水平均明显降低，与治疗前相比差别具有显著性。本研究说明CN-AML中对GATA2和CBP的动态监测可作为评价治疗效果和预测复发的指标。
3初治组CN-AML中GATA2和CBP的表达量之间存在秩相关。目前我们可以认为GATA2和CBP在白血病的发病过程中共同发挥作用。CBP作为GATA2的辅激活因子应用于急性白血病中，并可联合GATA2共同预测CN-AML预后。
Objective： Acute myeloid leukemia (AML) is a tumor of highlymalignant cloning proliferation. In recent years， with the popularity ofmolecular biology techniques， the number of gene mutations and abnormalgene expression (including FLT3mutations, NPM1and CEBPA) were foundin patients with normal karyotype acute myeloid leukemia (CN-AML)., andsignificantly affect the clinical outcome. The discovery and study of molecularmarkers provides an important basis for the CN-AML diagnosis, treatment andprognosis.
The biological functions of GATA2in hematopoietis and the importanceof its balanced expression led to the suggestion that it might be involved inleukemogenesis. Since GATA2levels decreased with differentiation in each ofthe various hematopoietic sub-lineages, this pattern might reflect the ability ofoverexpressed or activated GATA2to suppress normal differentiation andpromote leukemic transformation. CREB-binding proteins (CBP) as atranscriptional coactivator of GATA-2。CBP is a transcription adaptor by directbridging between basic transcription factors and several sequence-specifictranscriptional activator. Both in vivo or in vitro CBP can combination withGATA-2, and be able to improve the activity of GATA-2transcriptionalactivation in a dose-dependent manner. CBP protein expression of GATA-2selective binding to maintain the undifferentiated state of hematopoietic cells,it is this state of hematopoietic progenitor cells and development mechanismwill help us to control the leukemia and abnormal differentiation ofhematopoietic progenitor cells diseases. The study was to investigate therelationship between the expression of GATA-2/CBP and the development ofacute leukemia, then to investigate whether there was some relationship between the coexpression of GATA-2/CBP and the pathogenesis of acuteleukemia. Multi-angle and other aspects of cell development, proliferation,differentiation-depth study of the expression characteristics of the GATA-2and CBP in the development of acute leukemia, which gradually clear itsmechanism, to provide new ideas for the treatment of CN-AML and toimprove the cure of leukemiarate and long-term disease-free survival lay thefoundation。
Methods:1Collect bone marrow fluid samples of2011.4-2012.1part inthe Second Hospital of Hebei Medical University, inpatient and outpatient fora total of87cases of AML patients(including34cases of untreated CN-AMLpatients,45cases of complete remission patients,8cases of relapse CN-AMLpatients), and11cases of normal group (patients with non-hematologicmalignancies).
2Using the lymphocyte separation medium separation of bone marrowmononuclear cells;
3Semi-quantitative reverse transcription-polymerase chain reaction（RT-PCR）to detect GATA2and CBP mRNA levels of each group;
4Statistically
Results:1The expression level of GATA2mRNA in each group
1.1The expression of GATA2mRNA in de novo CN-AML patients(mean1.299（1.469）,positive rate97.1%) and in relapse (RP) CN-AMLpatients (mean1.367（1.734）,positive rate100%). There was no differencebetween de novo and RP group。But de novo group were significantly higherthan NC (mean0.592（0.916）, positive rate54.5%)(P <0.05). The expressionof GATA2mRNA in CR group （mean0.412(1.079), positive rate88.9%）were lower than that in de novo CN-AML patients (P<0.05). But there was nodifference between CR group and NC group(P>0.05)。
1.2The de novo CN-AML patients were divided into GATA2highexpression group and GATA2low expression group. The CR rate was92.31%in GATA2high expression group, The CR rate was75%in GATA2lowexpression group, there was no difference between the GATA2high expression group and GATA2low expression group (P>0.05).
2The expression level of CBP mRNA in each group
2.1The mean expression of CBP mRNA in de novo CN-AML patientswas1.070（1.661）, the positive rate was97.1%（33/34）. In the RP-patients,the mean expression was1.546（0.347）, the positive rate was100%（8/8）. Inthe CR-patients, the mean expression was0.451（0.908）, the positive rate was93.3%（42/45）. In the NC group, they were0.591（0.358） and100%（11/11）separately. In addition to the de novo group and the RP group, the CR groupand the NC group, CBP mRNA expression level in the rest of each group inthe AL have significantly difference.
2.2The de novo CN-AML patients were divided into CBP highexpression group and CBP low expression group. The CR rate was83.33%inCBP high expression group, and there was no difference between the CBPhigh expression group and the CBP low expression group (CR rate80.95%)(P>0.05).
3There were94.12%de novo CN-AML patients measured to expressboth GATA2and CBP mRNA.
4There was no correlated between GATA2, CBP expression level andthe white blood cell count, hemoglobin, platelet count and the original numberof immature cells in the de novo group (P>0.05). Detected18CN-AMLpatients, GATA2and CBP mRNA expression level and CD34+cell countWere related to analysis, we find that there is no significant correlation (P>0.05)。
5The expression level of GATA2and CBP in the de novo group andCR group
Tracking observation the16patients with CN-AML, detected theGATA2and CBP expression level of bone marrow mononuclear cells inthe de novo group and CR group. The results showed that GATA2expressionlevels in the de novo group is1.699（1.243）, Significantly lower than the denovo group, the difference was statistically significant (P <0.05). CBPexpression levels in the de novo group is1.437（2.160）, To ease after the CBP expression level is0.323(0.919)，was significantly lower than beforetreatment, the difference was statistically significant (P <0.05)。
Conclusions:
1In de novo and relapsed CN-AML patients, the expression of GATA2mRNA abnormally increases; however，the expression is lower in completeremission group, there is no difference compared with normal group. Theexpression of CBP mRNA in de novo and relapsed patients are higher than inthe normal group and remission patients, the difference between the groupsare statistically significant. In summary, GATA2and CBP may play a moreimportant role， and provide a theoretical basis for the AML stratifiedtreatment.
2The expression level of GATA2and CBP does not affect the CRrate.Compared with the expression before chemotherapy, the expression oftwo genes obviously decrease after complete remission. Dynamic monitoringGATA2and CBP mRNA can be used as indicators to evaluate the therapeuticeffect and predict recurrence.
3The expression level of GATA2and CBP mRNA in de novo CN-AMLpatients is correlation. At present, we can assume that GATA2and CBPjointly play a role in the pathogenesis of leukemia. CBP，as a new molecularmarker used in acute leukemia, can be joint GATA2to predict the prognosisof CN-AML.
引文
1Lee ME, Temizer DH, Clifford JA, et al. Cloning of the GATA-bindingprotein that regulates endothelin-1gene expression in endothelialcells[J]. J Biol Chem,1991,266(24):16188-92
2Pedone PV, Omichinski JG, Nony P, et al. The N-terminal fingers ofchicken GATA-2and GATA-3are independent sequence-specific DNAbinding domains[J]. EMBO J,1997,16(10):2874-82
3Minegishi N, Ohta J, Suwabe N, et al. Alternative promoters regulatetranscription of the mouse GATA-2gene[J]. J Biol Chem,1998,273(6):3625-34
4Tsai FY, Keller G, Kuo FC, et al. An early haematopoietic defect inmice lacking the transcription factor GATA-2[J]. Nature,1994,371(6494):221-6
5Tsai FY, Orkin SH. Transcription factor GATA-2is required forproliferation/survival of early hematopoietic cells and mast cellformation, but not for erythroid and myeloid terminal differentiation[J].Blood,1997,89(10):3636-43
6Kumano K, Chiba S, Shimizu K, et al. Notch1inhibits differentiationof hematopoietic cells by sustaining GATA-2expression[J]. Blood,2001,98(12):3283-9
7Tsai FY, Keller G, Kuo FC, et al. An early haematopoietic defect inmice lacking the transcription factor GATA-2[J]. Nature,1994,371(6494):221-6
8Li Y, Wang M. The Role of Transcription Factor GATA-2in EarlyHematopoiesis[J]. Zhongguo Shi Yan Xue Ye Xue Za Zhi,2000,8(1):66-70
9Kelley C, Yee K, Harland R, et al. Ventral expression of GATA-1andGATA-2in the Xenopus embryo defines induction of hematopoieticmesoderm[J]. Dev Biol,1994,165(1):193-205
10Shimamoto T, Ohyashiki K, Ohyashiki JH, et al. The expressionpattern of erythrocyte/megakaryocyte-related transcription factorsGATA-1and the stem cell leukemia gene correlates with hematopoieticdifferentiation and is associated with outcome of acute myeloidleukemia[J]. Blood,1995,86(8):3173-80
11Rebel VI, Kung AL, Tanner EA, et al. Distinct roles for CREB-bindingprotein and p300in hematopoietic stem cell self-renewal[J]. Proc NatlAcad Sci U S A,2002,99(23):14789-94
12Chrivia JC, Kwok RP, Lamb N, et al. Phosphorylated CREB bindsspecifically to the nuclear protein CBP[J]. Nature,1993,365(6449):855-9
13Boyes J, Byfield P, Nakatani Y, et al. Regulation of activity of thetranscription factor GATA-1by acetylation[J]. Nature,1998,396(6711):594-8
14Grass JA, Boyer ME, Pal S, et al. GATA-1-dependent transcriptionalrepression of GATA-2via disruption of positive autoregulation anddomain-wide chromatin remodeling[J]. Proc Natl Acad Sci U S A,2003,100(15):8811-6
15Borrow J, Stanton VP Jr, Andresen JM, et al. The translocationt(8;16)(p11;p13) of acute myeloid leukaemia fuses a putativeacetyltransferase to the CREB-binding protein[J]. Nat Genet,1996,14(1):33-41
16Panagopoulos I, Fioretos T, Isaksson M, et al. Fusion of the MORF andCBP genes in acute myeloid leukemia with the t(10;16)(q22;p13)[J].Hum Mol Genet,2001,10(4):395-404
17Eckner R, Ewen ME, Newsome D, et al. Molecular cloning andfunctional analysis of the adenovirus E1A-associated300-kD protein(p300) reveals a protein with properties of a transcriptional adaptor[J].Genes Dev,1994,8(8):869-84
1Wickrema A, Crispino JD. Erythroid and megakaryocytictransformation. Oncogene.2007.26(47):6803-15
2Rosenbauer F, Tenen DG. Transcription factors in myeloiddevelopment: balancing differentiation with transformation. Nat RevImmunol.2007.7(2):105-17
3Ko LJ, Engel JD. DNA-binding specificities of the GATA transcriptionfactor family. Mol Cell Biol.1993.13(7):4011-22
4Weiss MJ, Orkin SH. GATA transcription factors: key regulators ofhematopoiesis. Exp Hematol.1995.23(2):99-107
5Ling KW, Ottersbach K, van HJP, et al. GATA-2plays two functionallydistinct roles during the ontogeny of hematopoietic stem cells. J ExpMed.2004.200(7):871-82
6Pandolfi PP, Roth ME, Karis A, et al. Targeted disruption of theGATA3gene causes severe abnormalities in the nervous system andin fetal liver haematopoiesis. Nat Genet.1995.11(1):40-4
7Lee ME, Temizer DH, Clifford JA, Quertermous T. Cloning of theGATA-binding protein that regulates endothelin-1gene expression inendothelial cells. J Biol Chem.1991.266(24):16188-92
8Minegishi N, Ohta J, Suwabe N, et al. Alternative promoters regulatetranscription of the mouse GATA-2gene. J Biol Chem.1998.273(6):3625-34
9Minegishi N, Ohta J, Yamagiwa H, et al. The mouse GATA-2gene isexpressed in the para-aortic splanchnopleura and aorta-gonads andmesonephros region. Blood.1999.93(12):4196-207
10Pedone PV, Omichinski JG, Nony P, et al. The N-terminal fingers ofchicken GATA-2and GATA-3are independent sequence-specific DNAbinding domains. EMBO J.1997.16(10):2874-82
11Kobayashi-Osaki M, Ohneda O, Suzuki N, et al. GATA motifs regulateearly hematopoietic lineage-specific expression of the Gata2gene. MolCell Biol.2005.25(16):7005-20
12Zhou Y, Lim KC, Onodera K, et al. Rescue of the embryonic lethalhematopoietic defect reveals a critical role for GATA-2in urogenitaldevelopment. EMBO J.1998.17(22):6689-700
13Snow JW, Trowbridge JJ, Fujiwara T, et al. A single cis elementmaintains repression of the key developmental regulator Gata2.LID-e1001103[pii]. PLoS Genet.2010.6(9)
14Snow JW, Trowbridge JJ, Johnson KD, et al. Context-dependentfunction of "GATA switch" sites in vivo. Blood.2011.117(18):4769-72
15Kaneko H, Shimizu R, Yamamoto M. GATA factor switching duringerythroid differentiation. Curr Opin Hematol.2010.17(3):163-8
16Grass JA, Boyer ME, Pal S, Wu J, Weiss MJ, Bresnick EH.GATA-1-dependent transcriptional repression of GATA-2viadisruption of positive autoregulation and domain-wide chromatinremodeling. Proc Natl Acad Sci U S A.2003.100(15):8811-6
17Tsang AP, Fujiwara Y, Hom DB, Orkin SH. Failure ofmegakaryopoiesis and arrested erythropoiesis in mice lacking theGATA-1transcriptional cofactor FOG. Genes Dev.1998.12(8):1176-88
18Cantor AB, Iwasaki H, Arinobu Y, et al. Antagonism of FOG-1andGATA factors in fate choice for the mast cell lineage. J Exp Med.2008.205(3):611-24
19Koga S, Yamaguchi N, Abe T, et al. Cell-cycle-dependent oscillation ofGATA2expression in hematopoietic cells. Blood.2007.109(10):4200-8
20Menghini R, Marchetti V, Cardellini M, et al. Phosphorylation ofGATA2by Akt increases adipose tissue differentiation and reducesadipose tissue-related inflammation: a novel pathway linking obesityto atherosclerosis. Circulation.2005.111(15):1946-53
21Hayakawa F, Towatari M, Ozawa Y, Tomita A, Privalsky ML, Saito H.Functional regulation of GATA-2by acetylation. J Leukoc Biol.2004.75(3):529-40
22Chun TH, Itoh H, Subramanian L, Iniguez-Lluhi JA, Nakao K.Modification of GATA-2transcriptional activity in endothelial cells bythe SUMO E3ligase PIASy. Circ Res.2003.92(11):1201-8
23Pase L, Layton JE, Kloosterman WP, Carradice D, Waterhouse PM,Lieschke GJ. miR-451regulates zebrafish erythroid maturation in vivovia its target gata2. Blood.2009.113(8):1794-804
24Ikonomi P, Noguchi CT, Miller W, Kassahun H, Hardison R, SchechterAN. Levels of GATA-1/GATA-2transcription factors modulateexpression of embryonic and fetal hemoglobins. Gene.2000.261(2):277-87
25Ikonomi P, Rivera CE, Riordan M, Washington G, Schechter AN,Noguchi CT. Overexpression of GATA-2inhibits erythroid andpromotes megakaryocyte differentiation. Exp Hematol.2000.28(12):1423-31
26Ghatpande S, Ghatpande A, Sher J, Zile MH, Evans T. Retinoidsignaling regulates primitive (yolk sac) hematopoiesis. Blood.2002.99(7):2379-86
27Ezoe S, Matsumura I, Nakata S, et al. GATA-2/estrogen receptorchimera regulates cytokine-dependent growth of hematopoietic cellsthrough accumulation of p21(WAF1) and p27(Kip1) proteins. Blood.2002.100(10):3512-20
28Ohneda K, Yamamoto M. Roles of hematopoietic transcription factorsGATA-1and GATA-2in the development of red blood cell lineage.Acta Haematol.2002.108(4):237-45
29Terui K, Takahashi Y, Kitazawa J, Toki T, Yokoyama M, Ito E.Expression of transcription factors during megakaryocyticdifferentiation of CD34+cells from human cord blood induced bythrombopoietin. Tohoku J Exp Med.2000.192(4):259-73
30Huang Z, Dore LC, Li Z, et al. GATA-2reinforces megakaryocytedevelopment in the absence of GATA-1. Mol Cell Biol.2009.29(18):5168-80
31Chou ST, Khandros E, Bailey LC, et al. Graded repression ofPU.1/Sfpi1gene transcription by GATA factors regulateshematopoietic cell fate. Blood.2009.114(5):983-94
32Tsuzuki S, Enver T. Interactions of GATA-2with the promyelocyticleukemia zinc finger (PLZF) protein, its homologue FAZF, and thet(11;17)-generated PLZF-retinoic acid receptor alpha oncoprotein.Blood.2002.99(9):3404-10
33Zhang SJ, Shi JY, Li JY. GATA-2L359V mutation is exclusivelyassociated with CML progression but not other hematologicalmalignancies and GATA-2P250A is a novel single nucleotidepolymorphism. Leuk Res.2009.33(8):1141-3
34Fadilah SA, Cheong SK, Roslan H, Rozie-Hanisa M, Yen GK.GATA-1and GATA-2gene expression is related to the severity ofdysplasia in myelodysplastic syndrome. Leukemia.2002.16(8):1563-5
35Vicente C, Vazquez I, Conchillo A, et al. Overexpression of GATA2predicts an adverse prognosis for patients with acute myeloid leukemiaand it is associated with distinct molecular abnormalities. Leukemia.2012.26(3):550-4
36Shimamoto T, Ohyashiki K, Ohyashiki JH, et al. The expressionpattern of erythrocyte/megakaryocyte-related transcription factorsGATA-1and the stem cell leukemia gene correlates with hematopoieticdifferentiation and is associated with outcome of acute myeloidleukemia. Blood.1995.86(8):3173-80
37Ayala RM, Martinez-Lopez J, Albizua E, Diez A, Gilsanz F. Clinicalsignificance of Gata-1, Gata-2, EKLF, and c-MPL expression in acutemyeloid leukemia. Am J Hematol.2009.84(2):79-86
38Holash J, Wiegand SJ, Yancopoulos GD. New model of tumorangiogenesis: dynamic balance between vessel regression and growthmediated by angiopoietins and VEGF. Oncogene.1999.18(38):5356-62
39Connelly JJ, Wang T, Cox JE, et al. GATA2is associated with familialearly-onset coronary artery disease. PLoS Genet.2006.2(8): e139
40Hoshino T, Shimizu R, Ohmori S, et al. Reduced BMP4abundance inGata2hypomorphic mutant mice result in uropathies resemblinghuman CAKUT. Genes Cells.2008.13(2):159-70
2Pedone PV, Omichinski JG, Nony P, et al. The N-terminal fingers ofchicken GATA-2and GATA-3are independent sequence-specific DNAbinding domains[J]. EMBO J,1997,16(10):2874-82
3Minegishi N, Ohta J, Suwabe N, et al. Alternative promoters regulatetranscription of the mouse GATA-2gene[J]. J Biol Chem,1998,273(6):3625-34
4Tsai FY, Keller G, Kuo FC, et al. An early haematopoietic defect inmice lacking the transcription factor GATA-2[J]. Nature,1994,371(6494):221-6
5Tsai FY, Orkin SH. Transcription factor GATA-2is required forproliferation/survival of early hematopoietic cells and mast cellformation, but not for erythroid and myeloid terminal differentiation[J].Blood,1997,89(10):3636-43
6Kumano K, Chiba S, Shimizu K, et al. Notch1inhibits differentiationof hematopoietic cells by sustaining GATA-2expression[J]. Blood,2001,98(12):3283-9
7Tsai FY, Keller G, Kuo FC, et al. An early haematopoietic defect inmice lacking the transcription factor GATA-2[J]. Nature,1994,371(6494):221-6
8Li Y, Wang M. The Role of Transcription Factor GATA-2in EarlyHematopoiesis[J]. Zhongguo Shi Yan Xue Ye Xue Za Zhi,2000,8(1):66-70
9Kelley C, Yee K, Harland R, et al. Ventral expression of GATA-1andGATA-2in the Xenopus embryo defines induction of hematopoieticmesoderm[J]. Dev Biol,1994,165(1):193-205
10Shimamoto T, Ohyashiki K, Ohyashiki JH, et al. The expressionpattern of erythrocyte/megakaryocyte-related transcription factorsGATA-1and the stem cell leukemia gene correlates with hematopoieticdifferentiation and is associated with outcome of acute myeloidleukemia[J]. Blood,1995,86(8):3173-80
11Rebel VI, Kung AL, Tanner EA, et al. Distinct roles for CREB-bindingprotein and p300in hematopoietic stem cell self-renewal[J]. Proc NatlAcad Sci U S A,2002,99(23):14789-94
12Chrivia JC, Kwok RP, Lamb N, et al. Phosphorylated CREB bindsspecifically to the nuclear protein CBP[J]. Nature,1993,365(6449):855-9
13Boyes J, Byfield P, Nakatani Y, et al. Regulation of activity of thetranscription factor GATA-1by acetylation[J]. Nature,1998,396(6711):594-8
14Grass JA, Boyer ME, Pal S, et al. GATA-1-dependent transcriptionalrepression of GATA-2via disruption of positive autoregulation anddomain-wide chromatin remodeling[J]. Proc Natl Acad Sci U S A,2003,100(15):8811-6
15Borrow J, Stanton VP Jr, Andresen JM, et al. The translocationt(8;16)(p11;p13) of acute myeloid leukaemia fuses a putativeacetyltransferase to the CREB-binding protein[J]. Nat Genet,1996,14(1):33-41
16Panagopoulos I, Fioretos T, Isaksson M, et al. Fusion of the MORF andCBP genes in acute myeloid leukemia with the t(10;16)(q22;p13)[J].Hum Mol Genet,2001,10(4):395-404
17Eckner R, Ewen ME, Newsome D, et al. Molecular cloning andfunctional analysis of the adenovirus E1A-associated300-kD protein(p300) reveals a protein with properties of a transcriptional adaptor[J].Genes Dev,1994,8(8):869-84
1Wickrema A, Crispino JD. Erythroid and megakaryocytictransformation. Oncogene.2007.26(47):6803-15
2Rosenbauer F, Tenen DG. Transcription factors in myeloiddevelopment: balancing differentiation with transformation. Nat RevImmunol.2007.7(2):105-17
3Ko LJ, Engel JD. DNA-binding specificities of the GATA transcriptionfactor family. Mol Cell Biol.1993.13(7):4011-22
4Weiss MJ, Orkin SH. GATA transcription factors: key regulators ofhematopoiesis. Exp Hematol.1995.23(2):99-107
5Ling KW, Ottersbach K, van HJP, et al. GATA-2plays two functionallydistinct roles during the ontogeny of hematopoietic stem cells. J ExpMed.2004.200(7):871-82
6Pandolfi PP, Roth ME, Karis A, et al. Targeted disruption of theGATA3gene causes severe abnormalities in the nervous system andin fetal liver haematopoiesis. Nat Genet.1995.11(1):40-4
7Lee ME, Temizer DH, Clifford JA, Quertermous T. Cloning of theGATA-binding protein that regulates endothelin-1gene expression inendothelial cells. J Biol Chem.1991.266(24):16188-92
8Minegishi N, Ohta J, Suwabe N, et al. Alternative promoters regulatetranscription of the mouse GATA-2gene. J Biol Chem.1998.273(6):3625-34
9Minegishi N, Ohta J, Yamagiwa H, et al. The mouse GATA-2gene isexpressed in the para-aortic splanchnopleura and aorta-gonads andmesonephros region. Blood.1999.93(12):4196-207
10Pedone PV, Omichinski JG, Nony P, et al. The N-terminal fingers ofchicken GATA-2and GATA-3are independent sequence-specific DNAbinding domains. EMBO J.1997.16(10):2874-82
11Kobayashi-Osaki M, Ohneda O, Suzuki N, et al. GATA motifs regulateearly hematopoietic lineage-specific expression of the Gata2gene. MolCell Biol.2005.25(16):7005-20
12Zhou Y, Lim KC, Onodera K, et al. Rescue of the embryonic lethalhematopoietic defect reveals a critical role for GATA-2in urogenitaldevelopment. EMBO J.1998.17(22):6689-700
13Snow JW, Trowbridge JJ, Fujiwara T, et al. A single cis elementmaintains repression of the key developmental regulator Gata2.LID-e1001103[pii]. PLoS Genet.2010.6(9)
14Snow JW, Trowbridge JJ, Johnson KD, et al. Context-dependentfunction of "GATA switch" sites in vivo. Blood.2011.117(18):4769-72
15Kaneko H, Shimizu R, Yamamoto M. GATA factor switching duringerythroid differentiation. Curr Opin Hematol.2010.17(3):163-8
16Grass JA, Boyer ME, Pal S, Wu J, Weiss MJ, Bresnick EH.GATA-1-dependent transcriptional repression of GATA-2viadisruption of positive autoregulation and domain-wide chromatinremodeling. Proc Natl Acad Sci U S A.2003.100(15):8811-6
17Tsang AP, Fujiwara Y, Hom DB, Orkin SH. Failure ofmegakaryopoiesis and arrested erythropoiesis in mice lacking theGATA-1transcriptional cofactor FOG. Genes Dev.1998.12(8):1176-88
18Cantor AB, Iwasaki H, Arinobu Y, et al. Antagonism of FOG-1andGATA factors in fate choice for the mast cell lineage. J Exp Med.2008.205(3):611-24
19Koga S, Yamaguchi N, Abe T, et al. Cell-cycle-dependent oscillation ofGATA2expression in hematopoietic cells. Blood.2007.109(10):4200-8
20Menghini R, Marchetti V, Cardellini M, et al. Phosphorylation ofGATA2by Akt increases adipose tissue differentiation and reducesadipose tissue-related inflammation: a novel pathway linking obesityto atherosclerosis. Circulation.2005.111(15):1946-53
21Hayakawa F, Towatari M, Ozawa Y, Tomita A, Privalsky ML, Saito H.Functional regulation of GATA-2by acetylation. J Leukoc Biol.2004.75(3):529-40
22Chun TH, Itoh H, Subramanian L, Iniguez-Lluhi JA, Nakao K.Modification of GATA-2transcriptional activity in endothelial cells bythe SUMO E3ligase PIASy. Circ Res.2003.92(11):1201-8
23Pase L, Layton JE, Kloosterman WP, Carradice D, Waterhouse PM,Lieschke GJ. miR-451regulates zebrafish erythroid maturation in vivovia its target gata2. Blood.2009.113(8):1794-804
24Ikonomi P, Noguchi CT, Miller W, Kassahun H, Hardison R, SchechterAN. Levels of GATA-1/GATA-2transcription factors modulateexpression of embryonic and fetal hemoglobins. Gene.2000.261(2):277-87
25Ikonomi P, Rivera CE, Riordan M, Washington G, Schechter AN,Noguchi CT. Overexpression of GATA-2inhibits erythroid andpromotes megakaryocyte differentiation. Exp Hematol.2000.28(12):1423-31
26Ghatpande S, Ghatpande A, Sher J, Zile MH, Evans T. Retinoidsignaling regulates primitive (yolk sac) hematopoiesis. Blood.2002.99(7):2379-86
27Ezoe S, Matsumura I, Nakata S, et al. GATA-2/estrogen receptorchimera regulates cytokine-dependent growth of hematopoietic cellsthrough accumulation of p21(WAF1) and p27(Kip1) proteins. Blood.2002.100(10):3512-20
28Ohneda K, Yamamoto M. Roles of hematopoietic transcription factorsGATA-1and GATA-2in the development of red blood cell lineage.Acta Haematol.2002.108(4):237-45
29Terui K, Takahashi Y, Kitazawa J, Toki T, Yokoyama M, Ito E.Expression of transcription factors during megakaryocyticdifferentiation of CD34+cells from human cord blood induced bythrombopoietin. Tohoku J Exp Med.2000.192(4):259-73
30Huang Z, Dore LC, Li Z, et al. GATA-2reinforces megakaryocytedevelopment in the absence of GATA-1. Mol Cell Biol.2009.29(18):5168-80
31Chou ST, Khandros E, Bailey LC, et al. Graded repression ofPU.1/Sfpi1gene transcription by GATA factors regulateshematopoietic cell fate. Blood.2009.114(5):983-94
32Tsuzuki S, Enver T. Interactions of GATA-2with the promyelocyticleukemia zinc finger (PLZF) protein, its homologue FAZF, and thet(11;17)-generated PLZF-retinoic acid receptor alpha oncoprotein.Blood.2002.99(9):3404-10
33Zhang SJ, Shi JY, Li JY. GATA-2L359V mutation is exclusivelyassociated with CML progression but not other hematologicalmalignancies and GATA-2P250A is a novel single nucleotidepolymorphism. Leuk Res.2009.33(8):1141-3
34Fadilah SA, Cheong SK, Roslan H, Rozie-Hanisa M, Yen GK.GATA-1and GATA-2gene expression is related to the severity ofdysplasia in myelodysplastic syndrome. Leukemia.2002.16(8):1563-5
35Vicente C, Vazquez I, Conchillo A, et al. Overexpression of GATA2predicts an adverse prognosis for patients with acute myeloid leukemiaand it is associated with distinct molecular abnormalities. Leukemia.2012.26(3):550-4
36Shimamoto T, Ohyashiki K, Ohyashiki JH, et al. The expressionpattern of erythrocyte/megakaryocyte-related transcription factorsGATA-1and the stem cell leukemia gene correlates with hematopoieticdifferentiation and is associated with outcome of acute myeloidleukemia. Blood.1995.86(8):3173-80
37Ayala RM, Martinez-Lopez J, Albizua E, Diez A, Gilsanz F. Clinicalsignificance of Gata-1, Gata-2, EKLF, and c-MPL expression in acutemyeloid leukemia. Am J Hematol.2009.84(2):79-86
38Holash J, Wiegand SJ, Yancopoulos GD. New model of tumorangiogenesis: dynamic balance between vessel regression and growthmediated by angiopoietins and VEGF. Oncogene.1999.18(38):5356-62
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