Shao Xuejun, Miao Meihua, Qi Xiaofei, Chen Zixing
The First Affiliated Hospital, Soochow University, Jiangsu Institute of Hematology, Jiangsu, P.R. China.
Oncol Lett. 2012 Aug;4(2):289-298. doi: 10.3892/ol.2012.736. Epub 2012 May 30.
Myelodysplastic syndrome (MDS) is a stem cell disease that has a characteristic morphological dysplasia. Adhesion molecules and the Wnt signaling pathway are mostly involved with the self-renewal, proliferation and differentiation of hematopoietic stem cells (HSCs) while Rho GTPases are closely correlated with the cytoskeleton and therefore cell morphology. To gain insight into the poorly understood pathophysiology of MDS, the present study focused on analyzing the gene expression profiles of these molecules with whole genomic array using CD34(+) cells from MDS patients. These profiles showed that N-cadherin, E-cadherin and c-myc binding protein tended to be downregulated, whereas β-catenin, Ras-proximate-1 GTPase-activating protein (Rap1GAP), c-myc promoter binding protein, Rac1, Rac2 and CDC42 tended to be upregulated. However, no change in the expression of genes involved in the canonical Wnt signaling pathway, with the exception of β-catenin, was observed. The array results were confirmed by real-time quantitative polymerase chain reaction (RQ-PCR) using CD34(+) cells from a cohort of patients with MDS-refractory anemia (RA) [WHO (2008) RCUD, RCMD and MDS-U] who had normal karyotypes. Only Rap1GAP and Rac2 showed higher expression levels when mononuclear cells were used from another group of patients with MDS-RA [WHO (2008) RCUD, RCMD and MDS-U] who also had normal karyotypes. We believe that the cadherin-β-catenin-c-myc signaling axis is crucial in the hematopoiesis of HSCs in the early stages of MDS. In addition, Ras-proximate-1 (Rap1), which is negatively regulated by Rap1GAP, may serve as an initiator of this axis through interplay with cadherin. This pathway is strengthened by the upregulation of Rac2, which may allow the nuclear translocation of β-catenin. The aberrant expression of Rho GTPases may also be responsible for the dysplasia characteristics observed in MDS. This study provides vital and new insights into the pathophysiology of MDS. The two small G proteins, Rap1GAP and Rac2, may act as new molecular markers for the diagnosis of MDS.
骨髓增生异常综合征（MDS）是一种具有特征性形态发育异常的干细胞疾病。黏附分子和Wnt信号通路大多参与造血干细胞（HSC）的自我更新、增殖和分化，而Rho GTP酶与细胞骨架密切相关，进而与细胞形态相关。为深入了解人们知之甚少的MDS病理生理学，本研究着重使用MDS患者的CD34(+)细胞，通过全基因组阵列分析这些分子的基因表达谱。这些谱显示，N-钙黏蛋白、E-钙黏蛋白和c-myc结合蛋白倾向于下调，而β-连环蛋白、Ras-近端-1 GTP酶激活蛋白（Rap1GAP）、c-myc启动子结合蛋白、Rac1、Rac2和CDC42倾向于上调。然而，除β-连环蛋白外，未观察到经典Wnt信号通路相关基因表达的变化。使用来自一组核型正常的MDS难治性贫血（RA）[世界卫生组织（2008年）RCUD、RCMD和MDS-U]患者的CD34(+)细胞，通过实时定量聚合酶链反应（RQ-PCR）证实了阵列结果。当使用来自另一组核型也正常的MDS-RA[世界卫生组织（2008年）RCUD、RCMD和MDS-U]患者的单核细胞时，只有Rap1GAP和Rac2显示出较高的表达水平。我们认为，钙黏蛋白-β-连环蛋白-c-myc信号轴在MDS早期HSC的造血过程中至关重要。此外，受Rap1GAP负调控的Ras-近端-1（Rap1）可能通过与钙黏蛋白相互作用作为该信号轴的启动因子。Rac2的上调加强了该信号通路，这可能使β-连环蛋白发生核转位。Rho GTP酶的异常表达也可能是MDS中观察到的发育异常特征的原因。本研究为MDS的病理生理学提供了重要的新见解。两种小G蛋白Rap1GAP和Rac2可能作为MDS诊断的新分子标志物。
