儿童急性淋巴细胞白血病患者Midkine的表达及其与药物外排关系的研究
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摘要
研究背景
中期因子(MK)是近年来发现的肝素结合性生长因子,它与多向性生长因子(PTN)共同组成了MK家族。研究表明,MK在多种人类肿瘤组织中高表达,并参与肿瘤的发病过程。MK的生物学功能包括促进有丝分裂、促进转化、血管新生、抗凋亡和溶解纤维蛋白等。在急性髓细胞白血病(AML)细胞株和患者单个核细胞中发现有MK的异常表达,这意味着MK可能参与了白血病的发生、发展,但目前国内外关于儿童急性淋巴细胞白血病(ALL)患者MK表达情况的临床研究结果的报道却很少见。
多药耐药(MDR)目前仍然是治疗血液系统肿瘤的主要障碍之一,主要是指由一种药物诱发,引起对其它多种不同结构的药物同时产生交叉耐药,导致一些联合化疗方案失败的现象。导致MDR发生的主要机制是药物外排蛋白的过量表达引起了抗肿瘤药物的外排,其他机制包括细胞凋亡反应的改变、DNA修复的激活或药物作用靶点的变更等。目前研究显示MK通过抗凋亡、促进细胞生长、抗老化等作用促进肿瘤细胞对细胞毒药物的耐受,但关于MK影响肿瘤细胞对药物的外排能力的研究结果还未见报道。
目的
本研究通过检测MK在不同时期儿童ALL中的表达,研究MK在儿童ALL中的临床意义；同时测定MDRl基因的表达及观察不同个体对药物罗丹明123外排的功能,来探讨MK与白血病细胞对化疗药物外排作用的关系。
方法
选取2006年12月至2009年2月期间在中国医学科学院血液病医院就诊的153例初治及缓解期儿童ALL病例为实验对象,采用实时定量聚合酶链反应(real-time PCR)对患者及15例对照的骨髓标本行MK mRNA, MDR1mRNA的检测；选取其中30例B细胞(B-lineage) ALL初治患者和对照的单个核细胞,在激光共聚焦显微镜下观察这些细胞对药物罗丹明123的外排,并应用流式细胞仪测定细胞内的平均荧光强度(MFI)。
结果
通过实验观察和计算,对照组、B-lineage ALL完全缓解期患者组及B-lineageALL初治期患者组单个核细胞的MK mRNA的相对表达量呈现依次增高的现象,分别为0.795(0.697-1.570),3.012(0.932-5.076),12.909(2.385～26.347),三组数据的差异具有统计学意义(P<0.01)；而三组患者之间MDR1mRNA的水平未见明显差异。在罗丹明123的外排实验中发现B-lineage ALL初治患者组白血病细胞的MFI较对照组数据表现为明显减低(t=3.585,P<0.01)。患者白血病细胞中的MFI与MK mRNA水平表现为明显的负相关(r=-0.869,P<0.001)关系,与MDR1mRNA水平没有表现出相关关系。
结论
对儿童B-lineage ALL的研究发现：初治患者单个核细胞MK水平升高,完全缓解后MK水平减低,该基因的检测在临床中可作为儿童白血病疗效判定标准之一。高表达MK的白血病细胞药物外排能力较强,该因子可能影响儿童血液肿瘤中的化疗耐受,为临床中提高化疗药物敏感性提供了新的思路。初治患者MDR1的表达与Rh123外排没有表现出相关关系,参与儿童ALL多药耐药的其他转运蛋白需要进一步研究以明确。
Background:Midkine (MK) is a heparin-binding growth factor that was found rescent years as the product of a retinoic acid-responsive gene. It has45%sequence identity to pleiotrophin (PTN), and together PTN comprise a family of heparin-binding growth factors. In addition, it has been reported that MK exerts several cancer-related activities, including cell growth, survival, mitogenesis, transformation, angiogenesis, anti-apoptotosis, and fibrinolysis.
In acute myeloid leukemia (AML) cell lines and AML patients'cell, the abnormal expression of MK was found. So, MK may involve in the occurrence and development of acute leukemia. However there are a few reports about clinic study of MK expression in childhood acute lymphoblastic leukemia patients (ALL) at home and abroad,
multidrug resistance (MDR), ability of cancer cell to different chemotherapeutic drugs, is a major clinical obstacle in the treatment of hematological malignancies. And the main mechanism of MDR is the antineoplastic drug efflux induced by overexpression of drug transport proteins. Other mechanisms involved in MDR include alterations in the apoptotic response, activation of DNA repair or alterations in drug-target interactions. Numerous studies have been performed to confirm that MK promotes cancer cells to resistant to cytotoxic agents by anti-apoptotic, promoting cell growth, and anti-aging. However, it has never been reported that MK is associated with the ability of drug efflux of cancer cells.
Objective:To investigate the expression of midkine gene in childhood acute lymphoblastic leukemia patients (ALL) and to explore the clinical significance of midkine. To explore the possible effects of midkine (MK) gene on the chemotherapeutic drugs efflux in leukemia cells by observing Rh123efflux in different individuals.
Methods:A total of153children with ALL diagnosed in Blood Diseases Hospital, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College from December2006to February2009were enrolled in this study. Real-time quantitative PCR method was used to determine the expression of midkine and MDR1at mRNA level in patients and15control children. Meanwhile, laser scanning confocal microscope was used to observe the rhodamine123efflux from the leukemia cells in30new diagnosed B-lineage ALL patients and the mononuclear cells from15children with nonmalignant hematological diseases,(as control).
Results:Significant statistic difference in midkine gene expression was found among the normal group, the complete remission group and the de novo group, and the midkine levels were increased in turns (P<0.01). In the rhodamine123efflux test, mean fluorescence intensity (MFI) in the leukemia cells was obviously lower than that in normal cells and mere was an evident inverse correlation between the MFI and MK mRNA expression. Otherwise, there was no significant correlation between the MFI and MDR1mRNA expression.
Conclusions:MK expressed highly in new diagnosed B-lineage ALL patients, decreased in CR patients. MK gene level may be one of indexes to assess therapeutic effect. There was powerful efflux capability of rhodamine123in leukemia cells with high midkine gene expression.The midkine may participate in multidrug resistance. This study provided a new way to improve the sensitivity of chemotherapy in clinical treatment. But MDR1levels had no correlation with the degree of rhodamine123efflux, the futher experiments will be done to identify the other transportprotein contributing to MDR in children ALL.
中期因子(MK)是近年来发现的肝素结合性生长因子,它与多向性生长因子(PTN)共同组成了MK家族。研究表明,MK在多种人类肿瘤组织中高表达,并参与肿瘤的发病过程。MK的生物学功能包括促进有丝分裂、促进转化、血管新生、抗凋亡和溶解纤维蛋白等。在急性髓细胞白血病(AML)细胞株和患者单个核细胞中发现有MK的异常表达,这意味着MK可能参与了白血病的发生、发展,但目前国内外关于儿童急性淋巴细胞白血病(ALL)患者MK表达情况的临床研究结果的报道却很少见。
多药耐药(MDR)目前仍然是治疗血液系统肿瘤的主要障碍之一,主要是指由一种药物诱发,引起对其它多种不同结构的药物同时产生交叉耐药,导致一些联合化疗方案失败的现象。导致MDR发生的主要机制是药物外排蛋白的过量表达引起了抗肿瘤药物的外排,其他机制包括细胞凋亡反应的改变、DNA修复的激活或药物作用靶点的变更等。目前研究显示MK通过抗凋亡、促进细胞生长、抗老化等作用促进肿瘤细胞对细胞毒药物的耐受,但关于MK影响肿瘤细胞对药物的外排能力的研究结果还未见报道。
目的
本研究通过检测MK在不同时期儿童ALL中的表达,研究MK在儿童ALL中的临床意义；同时测定MDRl基因的表达及观察不同个体对药物罗丹明123外排的功能,来探讨MK与白血病细胞对化疗药物外排作用的关系。
方法
选取2006年12月至2009年2月期间在中国医学科学院血液病医院就诊的153例初治及缓解期儿童ALL病例为实验对象,采用实时定量聚合酶链反应(real-time PCR)对患者及15例对照的骨髓标本行MK mRNA, MDR1mRNA的检测；选取其中30例B细胞(B-lineage) ALL初治患者和对照的单个核细胞,在激光共聚焦显微镜下观察这些细胞对药物罗丹明123的外排,并应用流式细胞仪测定细胞内的平均荧光强度(MFI)。
结果
通过实验观察和计算,对照组、B-lineage ALL完全缓解期患者组及B-lineageALL初治期患者组单个核细胞的MK mRNA的相对表达量呈现依次增高的现象,分别为0.795(0.697-1.570),3.012(0.932-5.076),12.909(2.385～26.347),三组数据的差异具有统计学意义(P<0.01)；而三组患者之间MDR1mRNA的水平未见明显差异。在罗丹明123的外排实验中发现B-lineage ALL初治患者组白血病细胞的MFI较对照组数据表现为明显减低(t=3.585,P<0.01)。患者白血病细胞中的MFI与MK mRNA水平表现为明显的负相关(r=-0.869,P<0.001)关系,与MDR1mRNA水平没有表现出相关关系。
结论
对儿童B-lineage ALL的研究发现：初治患者单个核细胞MK水平升高,完全缓解后MK水平减低,该基因的检测在临床中可作为儿童白血病疗效判定标准之一。高表达MK的白血病细胞药物外排能力较强,该因子可能影响儿童血液肿瘤中的化疗耐受,为临床中提高化疗药物敏感性提供了新的思路。初治患者MDR1的表达与Rh123外排没有表现出相关关系,参与儿童ALL多药耐药的其他转运蛋白需要进一步研究以明确。
Background:Midkine (MK) is a heparin-binding growth factor that was found rescent years as the product of a retinoic acid-responsive gene. It has45%sequence identity to pleiotrophin (PTN), and together PTN comprise a family of heparin-binding growth factors. In addition, it has been reported that MK exerts several cancer-related activities, including cell growth, survival, mitogenesis, transformation, angiogenesis, anti-apoptotosis, and fibrinolysis.
In acute myeloid leukemia (AML) cell lines and AML patients'cell, the abnormal expression of MK was found. So, MK may involve in the occurrence and development of acute leukemia. However there are a few reports about clinic study of MK expression in childhood acute lymphoblastic leukemia patients (ALL) at home and abroad,
multidrug resistance (MDR), ability of cancer cell to different chemotherapeutic drugs, is a major clinical obstacle in the treatment of hematological malignancies. And the main mechanism of MDR is the antineoplastic drug efflux induced by overexpression of drug transport proteins. Other mechanisms involved in MDR include alterations in the apoptotic response, activation of DNA repair or alterations in drug-target interactions. Numerous studies have been performed to confirm that MK promotes cancer cells to resistant to cytotoxic agents by anti-apoptotic, promoting cell growth, and anti-aging. However, it has never been reported that MK is associated with the ability of drug efflux of cancer cells.
Objective:To investigate the expression of midkine gene in childhood acute lymphoblastic leukemia patients (ALL) and to explore the clinical significance of midkine. To explore the possible effects of midkine (MK) gene on the chemotherapeutic drugs efflux in leukemia cells by observing Rh123efflux in different individuals.
Methods:A total of153children with ALL diagnosed in Blood Diseases Hospital, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College from December2006to February2009were enrolled in this study. Real-time quantitative PCR method was used to determine the expression of midkine and MDR1at mRNA level in patients and15control children. Meanwhile, laser scanning confocal microscope was used to observe the rhodamine123efflux from the leukemia cells in30new diagnosed B-lineage ALL patients and the mononuclear cells from15children with nonmalignant hematological diseases,(as control).
Results:Significant statistic difference in midkine gene expression was found among the normal group, the complete remission group and the de novo group, and the midkine levels were increased in turns (P<0.01). In the rhodamine123efflux test, mean fluorescence intensity (MFI) in the leukemia cells was obviously lower than that in normal cells and mere was an evident inverse correlation between the MFI and MK mRNA expression. Otherwise, there was no significant correlation between the MFI and MDR1mRNA expression.
Conclusions:MK expressed highly in new diagnosed B-lineage ALL patients, decreased in CR patients. MK gene level may be one of indexes to assess therapeutic effect. There was powerful efflux capability of rhodamine123in leukemia cells with high midkine gene expression.The midkine may participate in multidrug resistance. This study provided a new way to improve the sensitivity of chemotherapy in clinical treatment. But MDR1levels had no correlation with the degree of rhodamine123efflux, the futher experiments will be done to identify the other transportprotein contributing to MDR in children ALL.
引文
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