RNA结合蛋白QKI在造血系统髓系分化中的表达调控及其功能研究
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摘要
髓系是造血系统分化发育过程中一支重要的谱系,其进一步分化成熟产生单核/巨噬细胞和粒细胞,这两类细胞是机体固有免疫的主要组成者,是机体实施免疫反应、炎症反应和创伤修复的重要分子,因此研究这两类细胞的分化有着重要的生理意义。而目前认为,在细胞因子的作用下,细胞内特定基因的表达或关闭在细胞分化过程中起着主导的地位,其调控异常是造血系统肿瘤发生启动因素和治疗靶点。因此发现和深入研究这些基因表达调控的机制有助于认识肿瘤发生发展机制,为肿瘤的防治提供重要依据.
QKI是一类RNA结合蛋白,由于其上游调控区的部分缺失引起组织特异性的QKI表达降低导致神经髓鞘发育障碍,小鼠出生后10天出现严重的震颤表型,故命名为QKI(quaking)。它属于RNA结合蛋白STAR(signals Transductions Activators of RNAs)家族,此蛋白结构具有结合上游蛋白激酶的SH3结构域,同时又具有RNA结合蛋白的结构特征,具有介导上游蛋白激酶和调控下游基因表达的双重角色,是重要的功能分子。目前对于它的研究大部分集中在中枢神经系统中。QKI主要通过调控髓鞘形成过程中重要分子,如MBP、MAG等的表达来参与髓鞘的形成。作为RNA结合蛋白,QKI对靶分子的调控主要是通过识别并结合于mRNA3’UTR上的特定序列即QKI反应元件(QRE)来调控其表达。这一调控发生在mRNA细胞内的定位、mRNA的稳定性以及翻译效率的改变等多个环节。
除了在神经系统外,QKI还在多种组织和器官中广泛表达,参与多个系统的发育和细胞增殖、分化与凋亡。一些ENU诱导的QKI纯合突变的小鼠出现胚胎致死表型,目前认为与卵黄囊时期的胚胎造血异常密切相关。在2005年发表于Nat Struct Mol Bio上的一篇文章中预测的众多QKI靶分子中,有部分与造血系统髓系分化密切相关。因此我们将QKI的研究集中在造血系统髓系的分化与发育上。
首先,我们在白血病细胞HL-60和THP-1的诱导分化模型中发现,造血系统髓系向单核/巨噬系和粒系分化过程中,QKI mRNA和蛋白表达水平均明显降低,可能与转录抑制有关。利用生物信息学分析QKI上游启动子区约2000bp,发现多个调控髓系分化的重要转录因子的结合位点;其中转录因子C/EBPα的表达水平变化与QKI一致,且QKI的变化发生在C/EBPα变化之后,提示QKI可能是C/EBPα的下游分子;进一步利用QKI启动子的荧光素酶报告系统检测和体内的ChIP实验进一步证实C/EBPα直接结合于QKI启动子距起始码ATG上游约1872bp-2036bp处上调其表达;随着分化的进程,由于C/EBPα的减少,结合于QKI启动子的C/EBPα减少,导致表达水平的下降。
单核/巨噬细胞分化过程中蛋白表达分析发现,决定单核/巨噬细胞谱系定向分化的特异性分子单核巨噬细胞集落刺激因子受体CSF1R( Macrophage-colony stimulating factor receptor,M-CSFR,又称为CSF1R)与QKI的表达趋势相反;在细胞内干涉或过表达QKI后,CSF1R也出现相反的表达变化,CSF1R是QKI的一个下游分子并受其负调控;在NCBI数据库中查找并比对不同种属间CSF1R3’UTR的序列,发现在人、牛、小鼠和猫之间同源性很高且均含有一个或两个QKI反应元件;将CSF1R3’UTR构建报告基因同时结合体内的RNA-IP实验证实QKI直接作用于CSF1R3’UTR降低其mRNA的稳定性而负调控CSF1R的表达。由此证实,在单核/巨噬细胞分化过程中,QKI表达水平的降低解除了对CSF1R mRNA的降解,使其表达水平升高,接受配体M-CSF信号的刺激,促使前体细胞一步步向单核/巨噬细胞分化。
粒细胞分化模型中发现,在10%血清条件下,ATRA诱导HL-60细胞不完全分化,以细胞周期阻滞为主要效应时,QKI表达无明显变化;在2%血清条件下,ATRA诱导绝大部分细胞分化为成熟的粒细胞,QKI在mRNA和蛋白水平均明显降低;改用另一较强的诱导分化剂DMSO,使大部分细胞快速分化为成熟的粒细胞时,QKI在mRNA和蛋白水平出现明显迅速的降低。由此看出,QKI的降低速度和程度与细胞分化的速度与程度呈正比;在这一过程中,QKI与C/EBPα的变化一致,因此QKI的降低与C/EBPα调控的减弱有关。另外,在粒系分化过程中,转入siRNA加速内源QKI的降低,细胞核形态检测发现前体细胞立即分化为成熟的粒细胞。由此初步得出结论,QKI在粒细胞的终末分化和活化中发挥重要调控作用。深入的机理研究正在进行当中。
此外,为了在血液细胞中实现QKI过表达来进行深入的功能研究,我们还构建和包装了过表达QKI的慢病毒,目前已能够成功感染贴壁细胞并实现稳定过表达QKI。
通过本课题的研究,首先,我们加深了对造血系统髓系分化的认识,首次提出RNA结合蛋白在这一过程中发挥重要作用。它不仅是受髓系分化重要转录因子C/EBPα直接调控的一个新的靶分子,还能够直接对细胞因子受体CSF1R进行转录后调控,决定单核/巨噬细胞能否正常分化;其次,进一步认识了转录后调控机制,发现了QKI新的功能和作用机制;再次,鉴于C/EBPα在细胞周期和脂肪等组织分化中的功能,及其CSF1R与生殖系统肿瘤和乳腺癌的发生密切相关,由此将QKI的功能研究拓展到多个领域,同时为相关疾病的诊治提供新的思路和治疗靶点;最后,我们还建立了慢病毒系统的平台,为后续实验提供有力的技术保障。
Myeloid lineage derived haematopoiesis, which produces monocyte/macrophage and granulocyte, is essential for the innate immunity and the wound healing. Although great advances have been made in the understandings of the myeloid differentiation process, the underlying mechanism is not fully understood. It has been widely accepted that cytokine related signal pathway influenced by both intrinsic and external stimuli is fundamental for normal hemopoietic differentiation. Aberrent expression of cytokine related signals leads to leukemia initiation. To this end, further exploring the underlying regulatory mechanism involved in the hemopoietic differentiation process will be valuable for leukemia prevention and treatment.
RNA binding protein QKI encoded by the quaking gene locus was designated from the quaking viable mice. Quaking viable (qkv) is an autosomal recessive mutation due to a deletion of the 5’flanking region of the qki gene, leading to diminished expression of the selective RNA-binding protein QKI in myelin producing cells and subsequently dysmyelination in the CNS. QKI harbors amino acid domains characteristic of RNA-binding and interaction with Src homology 3 (SH3)-containing signaling molecules, therefore belongs to a fast-growing family denoted as signal transduction activators of RNA (STAR). Currently, all the findings related with QKI are mainly focused on CNS, esp. related with MBP and MAG mRNA stability, splicing, translocation and translational repression during oligodentrocytes differentiation.. As RNA-binding protein, its interaction with target mRNA is mainly through binding with cis-element in target mRNA 3’UTR (Quaking Response Element, QRE).
However, the wide expression pattern of QKI in numerous tissues besides CNS implicates a fundamental role of QKI in other systems. In fact, the lethal phenotype in ENU-induced homozygous mutant qki mice highly proposed that QKI has a critical role in embryonic development prior to the start of myelination. It is now accepted that QKI plays an essential role in vascular development Interestingly, QKI is also expressed in the yolk sac endoderm, adjacent to the mesodermal site of developing blood islands, where early hemopoietic and endothelial cells originat from. All these data suggest a potential role of QKI in haematopoiesis. According to the predicted 1400 candidate target mRNAs published from Nat Stuct Mol Bio, many putative downstream target mRNAs are related with myeloid differentiation. Thus we focused on the role of QKI on the myeloid differentiation.
For the first time, in the leukemic cells HL-60 and THP-1, QKI expression level was down-regulated both at mRNA and protein levels during the myeloid differentiation towards monocyte/macrophage and granulocyte. To test whether transcriptional regulation is causal for such reduction,. QKI promoter with size of 2kb upstream to ATG start codon was analyzed by Bioinformatic methods, the results revealed that multiple haematopoietic differentiation related transcriptional factors are putative regulators of QKI. Among them, C/EBPαdisplayed a similar expression pattern with QKI. In addition, C/EBPαexpression level declined prior to the drop of QKI level, highly suggesting that C/EBPαis responsible for QKI transcriptional regulation. Then QKI promoter driven luciferase reporter readings and positive ChIP assay confirmed the direct transcriptional regulation of C/EBPαon QKI promoter region. Reduced expression of C/EBPαin the differentiated cells led to less C/EBPαoccupation on the QKI promoter and end up with down-regulation of QKI.
During myeloid differentiation process, there’s a reversed relationship between QKI and CSF1 R (Macrophage-colony stimulating factor receptor,M-CSFR) which is critical factor for the lineage decision. RNAi knocking down of QKI or over-expressing QKI, CSF1R showed reverse changes too. Analysis of the QREs located in the 3’UTR of CSF1R among multiple species disclosed that the QREs are highly conserved, suggesting a conservative regulation between QKI and CSF1R. CSF1R mRNA 3’UTR reporter assay and RNA-IP test further confirmed the direct interaction between QKI and CSF1R. The lengthened half-life of CSF1R supported that QKI mediated negative regulation on CSF1R is via mRNA stability alterations.
In the process of granulocyte differentiation, under 10% serum, ATRA induced HL-60 differentiation is not so dramatic but shows cell cycle arrest changes, at which time both C/EBPαand QKI showed a relative stable expression. While at 2% serum, the induced granulocyte showed more mature differentiation according to the marker gene level changes and nuclear staining pattern. Transfection of QKI RNAi acccelerated the differentiation process by the Giemmsa nuclear stainings. Further in-depth mechanism is undergoing.
In order to successfully over-express QKI in blood cells, lentivirus system encoding exogeneous QKI and EGFP was constructed and packaged. Purification of this lentivirus is now undergoing.
In summary, we first defined an important role of QKI in myeloid differentiation process.esp. it’s one of downstream target gene of C/EBPα., which belong to be a fate-decision factor. Further more, our findings provided the first direct evidence that QKI is responsible for destabilize CSF1R by direct interaction with its 3’UTR. Since cEBPαis also important for cell cycle regulation and adipocyte differentiation. Such regulation may also occur in other system. While CSF1R expression level changes is closely related with other types of cancer, such as breast cancer. QKI mediated regulation may be more practical for other systems.
QKI是一类RNA结合蛋白,由于其上游调控区的部分缺失引起组织特异性的QKI表达降低导致神经髓鞘发育障碍,小鼠出生后10天出现严重的震颤表型,故命名为QKI(quaking)。它属于RNA结合蛋白STAR(signals Transductions Activators of RNAs)家族,此蛋白结构具有结合上游蛋白激酶的SH3结构域,同时又具有RNA结合蛋白的结构特征,具有介导上游蛋白激酶和调控下游基因表达的双重角色,是重要的功能分子。目前对于它的研究大部分集中在中枢神经系统中。QKI主要通过调控髓鞘形成过程中重要分子,如MBP、MAG等的表达来参与髓鞘的形成。作为RNA结合蛋白,QKI对靶分子的调控主要是通过识别并结合于mRNA3’UTR上的特定序列即QKI反应元件(QRE)来调控其表达。这一调控发生在mRNA细胞内的定位、mRNA的稳定性以及翻译效率的改变等多个环节。
除了在神经系统外,QKI还在多种组织和器官中广泛表达,参与多个系统的发育和细胞增殖、分化与凋亡。一些ENU诱导的QKI纯合突变的小鼠出现胚胎致死表型,目前认为与卵黄囊时期的胚胎造血异常密切相关。在2005年发表于Nat Struct Mol Bio上的一篇文章中预测的众多QKI靶分子中,有部分与造血系统髓系分化密切相关。因此我们将QKI的研究集中在造血系统髓系的分化与发育上。
首先,我们在白血病细胞HL-60和THP-1的诱导分化模型中发现,造血系统髓系向单核/巨噬系和粒系分化过程中,QKI mRNA和蛋白表达水平均明显降低,可能与转录抑制有关。利用生物信息学分析QKI上游启动子区约2000bp,发现多个调控髓系分化的重要转录因子的结合位点;其中转录因子C/EBPα的表达水平变化与QKI一致,且QKI的变化发生在C/EBPα变化之后,提示QKI可能是C/EBPα的下游分子;进一步利用QKI启动子的荧光素酶报告系统检测和体内的ChIP实验进一步证实C/EBPα直接结合于QKI启动子距起始码ATG上游约1872bp-2036bp处上调其表达;随着分化的进程,由于C/EBPα的减少,结合于QKI启动子的C/EBPα减少,导致表达水平的下降。
单核/巨噬细胞分化过程中蛋白表达分析发现,决定单核/巨噬细胞谱系定向分化的特异性分子单核巨噬细胞集落刺激因子受体CSF1R( Macrophage-colony stimulating factor receptor,M-CSFR,又称为CSF1R)与QKI的表达趋势相反;在细胞内干涉或过表达QKI后,CSF1R也出现相反的表达变化,CSF1R是QKI的一个下游分子并受其负调控;在NCBI数据库中查找并比对不同种属间CSF1R3’UTR的序列,发现在人、牛、小鼠和猫之间同源性很高且均含有一个或两个QKI反应元件;将CSF1R3’UTR构建报告基因同时结合体内的RNA-IP实验证实QKI直接作用于CSF1R3’UTR降低其mRNA的稳定性而负调控CSF1R的表达。由此证实,在单核/巨噬细胞分化过程中,QKI表达水平的降低解除了对CSF1R mRNA的降解,使其表达水平升高,接受配体M-CSF信号的刺激,促使前体细胞一步步向单核/巨噬细胞分化。
粒细胞分化模型中发现,在10%血清条件下,ATRA诱导HL-60细胞不完全分化,以细胞周期阻滞为主要效应时,QKI表达无明显变化;在2%血清条件下,ATRA诱导绝大部分细胞分化为成熟的粒细胞,QKI在mRNA和蛋白水平均明显降低;改用另一较强的诱导分化剂DMSO,使大部分细胞快速分化为成熟的粒细胞时,QKI在mRNA和蛋白水平出现明显迅速的降低。由此看出,QKI的降低速度和程度与细胞分化的速度与程度呈正比;在这一过程中,QKI与C/EBPα的变化一致,因此QKI的降低与C/EBPα调控的减弱有关。另外,在粒系分化过程中,转入siRNA加速内源QKI的降低,细胞核形态检测发现前体细胞立即分化为成熟的粒细胞。由此初步得出结论,QKI在粒细胞的终末分化和活化中发挥重要调控作用。深入的机理研究正在进行当中。
此外,为了在血液细胞中实现QKI过表达来进行深入的功能研究,我们还构建和包装了过表达QKI的慢病毒,目前已能够成功感染贴壁细胞并实现稳定过表达QKI。
通过本课题的研究,首先,我们加深了对造血系统髓系分化的认识,首次提出RNA结合蛋白在这一过程中发挥重要作用。它不仅是受髓系分化重要转录因子C/EBPα直接调控的一个新的靶分子,还能够直接对细胞因子受体CSF1R进行转录后调控,决定单核/巨噬细胞能否正常分化;其次,进一步认识了转录后调控机制,发现了QKI新的功能和作用机制;再次,鉴于C/EBPα在细胞周期和脂肪等组织分化中的功能,及其CSF1R与生殖系统肿瘤和乳腺癌的发生密切相关,由此将QKI的功能研究拓展到多个领域,同时为相关疾病的诊治提供新的思路和治疗靶点;最后,我们还建立了慢病毒系统的平台,为后续实验提供有力的技术保障。
Myeloid lineage derived haematopoiesis, which produces monocyte/macrophage and granulocyte, is essential for the innate immunity and the wound healing. Although great advances have been made in the understandings of the myeloid differentiation process, the underlying mechanism is not fully understood. It has been widely accepted that cytokine related signal pathway influenced by both intrinsic and external stimuli is fundamental for normal hemopoietic differentiation. Aberrent expression of cytokine related signals leads to leukemia initiation. To this end, further exploring the underlying regulatory mechanism involved in the hemopoietic differentiation process will be valuable for leukemia prevention and treatment.
RNA binding protein QKI encoded by the quaking gene locus was designated from the quaking viable mice. Quaking viable (qkv) is an autosomal recessive mutation due to a deletion of the 5’flanking region of the qki gene, leading to diminished expression of the selective RNA-binding protein QKI in myelin producing cells and subsequently dysmyelination in the CNS. QKI harbors amino acid domains characteristic of RNA-binding and interaction with Src homology 3 (SH3)-containing signaling molecules, therefore belongs to a fast-growing family denoted as signal transduction activators of RNA (STAR). Currently, all the findings related with QKI are mainly focused on CNS, esp. related with MBP and MAG mRNA stability, splicing, translocation and translational repression during oligodentrocytes differentiation.. As RNA-binding protein, its interaction with target mRNA is mainly through binding with cis-element in target mRNA 3’UTR (Quaking Response Element, QRE).
However, the wide expression pattern of QKI in numerous tissues besides CNS implicates a fundamental role of QKI in other systems. In fact, the lethal phenotype in ENU-induced homozygous mutant qki mice highly proposed that QKI has a critical role in embryonic development prior to the start of myelination. It is now accepted that QKI plays an essential role in vascular development Interestingly, QKI is also expressed in the yolk sac endoderm, adjacent to the mesodermal site of developing blood islands, where early hemopoietic and endothelial cells originat from. All these data suggest a potential role of QKI in haematopoiesis. According to the predicted 1400 candidate target mRNAs published from Nat Stuct Mol Bio, many putative downstream target mRNAs are related with myeloid differentiation. Thus we focused on the role of QKI on the myeloid differentiation.
For the first time, in the leukemic cells HL-60 and THP-1, QKI expression level was down-regulated both at mRNA and protein levels during the myeloid differentiation towards monocyte/macrophage and granulocyte. To test whether transcriptional regulation is causal for such reduction,. QKI promoter with size of 2kb upstream to ATG start codon was analyzed by Bioinformatic methods, the results revealed that multiple haematopoietic differentiation related transcriptional factors are putative regulators of QKI. Among them, C/EBPαdisplayed a similar expression pattern with QKI. In addition, C/EBPαexpression level declined prior to the drop of QKI level, highly suggesting that C/EBPαis responsible for QKI transcriptional regulation. Then QKI promoter driven luciferase reporter readings and positive ChIP assay confirmed the direct transcriptional regulation of C/EBPαon QKI promoter region. Reduced expression of C/EBPαin the differentiated cells led to less C/EBPαoccupation on the QKI promoter and end up with down-regulation of QKI.
During myeloid differentiation process, there’s a reversed relationship between QKI and CSF1 R (Macrophage-colony stimulating factor receptor,M-CSFR) which is critical factor for the lineage decision. RNAi knocking down of QKI or over-expressing QKI, CSF1R showed reverse changes too. Analysis of the QREs located in the 3’UTR of CSF1R among multiple species disclosed that the QREs are highly conserved, suggesting a conservative regulation between QKI and CSF1R. CSF1R mRNA 3’UTR reporter assay and RNA-IP test further confirmed the direct interaction between QKI and CSF1R. The lengthened half-life of CSF1R supported that QKI mediated negative regulation on CSF1R is via mRNA stability alterations.
In the process of granulocyte differentiation, under 10% serum, ATRA induced HL-60 differentiation is not so dramatic but shows cell cycle arrest changes, at which time both C/EBPαand QKI showed a relative stable expression. While at 2% serum, the induced granulocyte showed more mature differentiation according to the marker gene level changes and nuclear staining pattern. Transfection of QKI RNAi acccelerated the differentiation process by the Giemmsa nuclear stainings. Further in-depth mechanism is undergoing.
In order to successfully over-express QKI in blood cells, lentivirus system encoding exogeneous QKI and EGFP was constructed and packaged. Purification of this lentivirus is now undergoing.
In summary, we first defined an important role of QKI in myeloid differentiation process.esp. it’s one of downstream target gene of C/EBPα., which belong to be a fate-decision factor. Further more, our findings provided the first direct evidence that QKI is responsible for destabilize CSF1R by direct interaction with its 3’UTR. Since cEBPαis also important for cell cycle regulation and adipocyte differentiation. Such regulation may also occur in other system. While CSF1R expression level changes is closely related with other types of cancer, such as breast cancer. QKI mediated regulation may be more practical for other systems.
引文
1.王绮如,谭孟群,程腊梅造血生理学中南大学出版社
2.刘厚奇,张远强,周国民医学发育生物学科学出版社
3.张之南,单渊东,李蓉生,潘家绮,武永吉协和血液病学中国协和医科大学
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19.陈子兴转录因子和造血分化调控及其意义国外医学·生理、病理科学与临床分册2003; 23(3):221-225.
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27. Xie H, Ye M, Feng R, Graf T. Stepwise reprogramming of B cells into macrophages. Cell. 2004;117:663–676.
28. Shih LY, Liang DC, Huang CF, Wu JH, Lin TL, Wang PN, Dunn P, Kuo MC, Tang TC.AML Datients with C/EBPαmutations mostly retain identica1 mutant patterns but frequently change in allelic distribution at relapse : a comparative analysis on paired diagnosis and relapse samples.Leukemia 2006;20:604-609.
29. Liang DC, Shih LY, Huang CF, Hung IJ, Yang CP, Liu HC, Jaing TH, Wang LY, Chang WH.C/EBPαmutations in childhood acute myeloid 1eukemia.Leukemia 2005;19:410-4l4.
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38.孙成铭,刘日明增强子结合蛋白C/EBPα与白血病临床血液学杂志2008; 21(6):333-336.
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2.刘厚奇,张远强,周国民医学发育生物学科学出版社
3.张之南,单渊东,李蓉生,潘家绮,武永吉协和血液病学中国协和医科大学
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13. Nuchprayoon I, Meyers S, Scott LM, Suzow J, Hiebert S, Friedman AD. PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2 beta/CBF beta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells. Mol Cell Biol. 1994;14:5558–5568.
14. Westendorf JJ, Yamamato CM, Lenny N, Downing JR, Selsted ME, Hiebert SW. The t(8;21) fusion product, AML-1-ETO, associates with C/EBP-α, inhibits C/EBP-α-dependent transcription, and blocks granulocytic differentiation. Mol Cell Biol. 1998;18:322–333.
15. Vangala RK, Heiss-Neumann MS, Rangatia JS, et al. The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Blood. 2003;101:270–277.
16. Zhu J, Emerson SG. Hematopoietic cytokines, transcription factors and lineage commitment. Oncogene. 2002;21:3295–3313.
17. Friedman AD. Transcriptional regulation of granulocyte and monocytedevelopment. Oncogene. 2002;21:3377–3390.
18. Skalnik DG. Transcriptional mechanisms regulating myeloid-specific genes. Gene. 2002;284:1–21.
19.陈子兴转录因子和造血分化调控及其意义国外医学·生理、病理科学与临床分册2003; 23(3):221-225.
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21. Johnson PF. Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. J Cell Sci. 2005;118(Pt 12):2545-2555.
22. Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG. CCAAT enhancer binding proteinαis a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol. 1998;18:4301–4314.
23. Muller C, Kowenz-Leutz E, Grieser-Ade S, Graf T, Leutz A. NF-M (chicken C/EBP beta) induces eosinophilic differentiation and apoptosis in a hematopoietic progenitor cell line. EMBO J. 1995;14:6127–6135.
24. Hohaus S, Petrovick MS,VosoMT, Sun Z, Zhang DE, Tenen DG. PU.1(Spi-1) and C/EBP alpha regulate expression of the granulocytemacrophage colony-stimulating factor receptor alpha gene. Mol Cell Biol. 1995;15:5830–5845.
25. Scott LM, Civin Cl, Rorth P, Friedman AD. A novel temporal expression pattern of three C/EBP family members in differentiating Myelomonocytic Cells. Blood. 1992;80:1725–1735.
26. Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG. CCAAT enhancer binding proteinαis a regulatory switch sufficient forinduction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol. 1998;18:4301–4314.
27. Xie H, Ye M, Feng R, Graf T. Stepwise reprogramming of B cells into macrophages. Cell. 2004;117:663–676.
28. Shih LY, Liang DC, Huang CF, Wu JH, Lin TL, Wang PN, Dunn P, Kuo MC, Tang TC.AML Datients with C/EBPαmutations mostly retain identica1 mutant patterns but frequently change in allelic distribution at relapse : a comparative analysis on paired diagnosis and relapse samples.Leukemia 2006;20:604-609.
29. Liang DC, Shih LY, Huang CF, Hung IJ, Yang CP, Liu HC, Jaing TH, Wang LY, Chang WH.C/EBPαmutations in childhood acute myeloid 1eukemia.Leukemia 2005;19:410-4l4.
30. Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, Behre G, Hiddemann W, Tenen DG. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha),in acute myeloid leukemia. Nat Genet. 2001;27:263-270.
31. Gombart AF, Hofmann WK, Kawano S, Takeuchi S, Krug U, Kwok SH, Larsen RJ, Asou H, Miller CW, Hoelzer D, Koeffler HP. Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias.Blood. 2002;99:1332-1340.
32. Snaddon J, Smith ML, Neat M, et al. Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2. Genes Chromosomes Cancer. 2003;37:72-78.
33. Preudhomme C, Sagot C, Boissel N, et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloidleukemia: a study from the Acute Leukemia French Association (ALFA). Blood. 2002;100:2717-2723.
34. Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia N Engl J Med,2004;35l:2403-2407.
35. Sellick GS, Spendlove HE, Catovsky D, Pritchard-Jones K, Houlston RS. Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia Leukemia 2005;l9:1276-l278.
36. Perrotti D, Cesi V, Trotta R, Guerzoni C, Santilli G, Campbell K, Iervolino A, Condorelli F, Gambacorti-Passerini C, Caligiuri MA, Calabretta B. BCRABL suppresses C/EBPαexpression through inhibitory action of hnRNP E2.Nat Genet.2002;30:48-58.
37. Wagner K, Zhang P, Rosenbauer F, Drescher B, Kobayashi S, Radomska HS, Kutok JL, Gilliland DG, Krauter J, Tenen DG. Absence of the transcription factor CCAAT enhancer binding protein d results in loss of myeloid identity in bcr/abl-induced malignancy.Proc Natl Acad Sci USA. 2006;l03:6338-6343.
38.孙成铭,刘日明增强子结合蛋白C/EBPα与白血病临床血液学杂志2008; 21(6):333-336.
39. Hohaus S, Petrovick MS,VosoMT, Sun Z, Zhang DE, Tenen DG. PU.1(Spi-1) and C/EBP alpha regulate expression of the granulocytemacrophage colony-stimulating factor receptor alpha gene. Mol Cell Biol. 1995;15:5830–5845.
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