CAJ | 학술논문

目的通过分析骨髓增生异常综合征(MDS)患者骨髓造血干/祖细胞造血调控相关基因表达谱,探讨MDS发生的病理生理机制.方法先采用全基因组表达谱芯片筛选MDS患者CD34+细胞造血调控相关差异表达基因,再用实时荧光定量PCR(RQ-PCR)法验证这些差异表达基因在核型正常的MDS-难治性贫血(RA)患者CD34+细胞中是否也存在差异表达,分析差异表达基因与造血调控的内在联系.结果 MDS-RA患者CD34+细胞Rap1GAP基因表达显著上调(P<0.01),而与Rap1存在反馈调节作用的黏附分子cadherin,包括N-cadherin和E-cadherin的表达显著下调(P值均<0.01),其下游靶分子β-catenin的表达显著增高(P<0.01).c-myc结合蛋白基因表达显著下调(P<0.01),c-myc 启动子结合蛋白基因表达显著上调(P<0.01).既参与造血,又与细胞形态密切相关的 RhoGTPases家族分子Rac1、Rac2和Cdc42的表达水平显著上调(P值均<0.01).结论 Cadherin、β-catenin和c-myc相关基因表达异常与MDS的病态造血密切相关,cadherin的下调与Rap1的正反馈调节相关,Rac1、Rac2和Cdc42基因表达异常可能与MDS骨髓细胞形态异常相关.
목적 통과분석골수증생이상종합정(MDS)환자골수조혈간/조세포조혈조공상관기인표체보,탐토MDS발생적병리생리궤제.방법 선채용전기인조표체보심편사선MDS환자CD34+세포조혈조공상관차이표체기인,재용실시형광정량PCR(RQ-PCR)법험증저사차이표체기인재핵형정상적MDS-난치성빈혈(RA)환자CD34+세포중시부야존재차이표체,분석차이표체기인여조혈조공적내재련계.결과 MDS-RA환자CD34+세포Rap1GAP기인표체현저상조(P<0.01),이여Rap1존재반궤조절작용적점부분자cadherin,포괄N-cadherin화E-cadherin적표체현저하조(P치균<0.01),기하유파분자β-catenin적표체현저증고(P<0.01).c-myc결합단백기인표체현저하조(P<0.01),c-myc 계동자결합단백기인표체현저상조(P<0.01).기삼여조혈,우여세포형태밀절상관적 RhoGTPases가족분자Rac1、Rac2화Cdc42적표체수평현저상조(P치균<0.01).결론 Cadherin、β-catenin화c-myc상관기인표체이상여MDS적병태조혈밀절상관,cadherin적하조여Rap1적정반궤조절상관,Rac1、Rac2화Cdc42기인표체이상가능여MDS골수세포형태이상상관.
Objective To explore the hematopoietic pathophysiology of myelodysplastic syndrome (MDS) at stem/progenitor cell level by analyzing the gene expression profiles associated with hematopoiesis. Methods The differentially expressed genes which were involved in the hematopoiesis were screened by microarray using CD34+ cells from MDS patients firstly. RQ-CR was then applied to validate the screened genes using CD34+ cells from MDS-RA patients who had normal karyotype. The linkages with hematopoiesis among these validated genes were analyzed. Results Among the differentially expressed genes in CD34+ cells of MDS-RA patients, Rap1GAP was up-regulated significantly(P<0.01). Cadherins, which cannterplay with Rap1, including N-cadherin and E-cadherin, were down-regulated significantly (P<0.01).Β-catenin, a downstream effector of cadherins, was highly expressed in MDS-RA patients(P<0.01). C-myc binding protein was down-regulated(P<0.01),and c-myc promoter binding protein was up-regulated(P<0.01). Rac1, Rac2 and Cdc42, which belong to RhoGTPases family and are associated with the cell morphology and hematopoiesis, were all expressed highly in MDS-RA patients(P<0.01). Conclusion The abnormal expression of cadherin, β-catenin and c-myc associated genes were closely related to the dysplastic hematopoiesis of MDS. The down egulation of cadherin was associated with the positive feedback mechanism between Rap1 and cadherin. The aberrant expression of Rac1, Rac2 and Cdc42 may contribute to the morphological dysplasia of MDS.