Bmi-1作为儿童急性淋巴细胞白血病预后分子标志物的研究
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摘要
目的:研究Bmi-1基因能否作为儿童ALL的临床风险分析和预后分析的生物标志物。方法:通过qRTPCR检测127例初诊ALL患儿骨髓标本中Bmi-1基因的表达水平,同时应用Western blot技术检测对应标本中Bmi-1蛋白的表达情况。根据不同的临床风险分级,将收集到的骨髓标本分为高危、中危、低危3组,分析Bmi-1的表达与ALL患儿临床风险分级之间的关系。根据强的松试验敏感性将标本分为敏感和不敏感2组,比较Bmi-1的表达在2组之间是否有差异。根据Bmi-1表达量的中位数,将标本分成高水平和低水平2组,依据Kaplan-Meier方法计算儿童ALL患者预后与Bmi-1表达水平的相关性。结果:低风险组Bmi-1表达水平最低;高风险组Bmi-1表达水平最高,中风险组Bmi-1表达水平介于低风险组和高风险组之间,且统计结果有显著性差异(P <0.05)。强的松试验不敏感组的表达明显高于强的松试验敏感组(P <0.001)。Bmi-1表达水平高的患者无复发存活率明显低于Bmi-1表达水平低的患者,前者为73.0%,后者为90.6%,在统计学方面有显著性差异(P<0.001)。结论:Bmi-1可以作为1种新的儿童ALL临床风险分析指标和预后的分子标志物。
Objective: To study whether the Bmi-1 gene can be a biomarker for analysis of clinical risk stratification and prognosis of ALL patients. Methods: The expression level of Bmi-1 gene in bone marrow samples from 127 cases of newly diagnosed ALL was detected by qRT-PCR, at the same time the expression level of Bmi-1 protein in bone marrow samples from above-mentioned cases was detected by Western blot. The collected samples were divided into 3 groups:high, intermediate and low risk according to clinical risk stratfication, the relationship between Bmi-1 expression and risk grade of ALL patients was analyzed; at the same time the collected samples were divided into 2 groups: prednisone good response(PGR) and prednisone poor respouse(PPR) according to the sensitivity of prednison test, and the sensitivily to prednisone in 2 groups was compared; moreover, the collected samples were divided into 2 groups: high level and low level according to median of Bmi-1 level, and the relation of Bmi-1 level with prognosis of patients was analyzed by using the Kaplan-Meier method. Results: The expression level of Bmi-1 in low risk group was lowest, while that in high risk group was highest, however that in intermediat risk group was between the low and high risk groups, statistical analysis showed significant difference(P<0.05). The expression level of Bmi-1 in PPR group was significantly higher than that in PGR group(P<0.001). The Kaplan-Meier analysis showed that the RFS rate in Bmi-1 high expression group was significantly lower than that in Bmi-1 low expression group(73.0% vs 90.6%)(P<0.001). Conclusion: The Bmi-1 can be used as a molecular marker for the analysis of chinical risk and prognosis of pediatric ALL.
Objective: To study whether the Bmi-1 gene can be a biomarker for analysis of clinical risk stratification and prognosis of ALL patients. Methods: The expression level of Bmi-1 gene in bone marrow samples from 127 cases of newly diagnosed ALL was detected by qRT-PCR, at the same time the expression level of Bmi-1 protein in bone marrow samples from above-mentioned cases was detected by Western blot. The collected samples were divided into 3 groups:high, intermediate and low risk according to clinical risk stratfication, the relationship between Bmi-1 expression and risk grade of ALL patients was analyzed; at the same time the collected samples were divided into 2 groups: prednisone good response(PGR) and prednisone poor respouse(PPR) according to the sensitivity of prednison test, and the sensitivily to prednisone in 2 groups was compared; moreover, the collected samples were divided into 2 groups: high level and low level according to median of Bmi-1 level, and the relation of Bmi-1 level with prognosis of patients was analyzed by using the Kaplan-Meier method. Results: The expression level of Bmi-1 in low risk group was lowest, while that in high risk group was highest, however that in intermediat risk group was between the low and high risk groups, statistical analysis showed significant difference(P<0.05). The expression level of Bmi-1 in PPR group was significantly higher than that in PGR group(P<0.001). The Kaplan-Meier analysis showed that the RFS rate in Bmi-1 high expression group was significantly lower than that in Bmi-1 low expression group(73.0% vs 90.6%)(P<0.001). Conclusion: The Bmi-1 can be used as a molecular marker for the analysis of chinical risk and prognosis of pediatric ALL.
引文
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4 Bruggeman SW,Hulsman D,Tanger E,et al.Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma.Cancer Cell,2007;12(4):328-341.
5 DiMauro T,Cantor DJ,Bainor AJ,et al.Transcriptional repression of Sin3B by Bmi-1 prevents cellular senescence and is relieved by oncogene activation.Oncogene,2015;34(30):4011-4017.
6 Song LB,Zeng MS,Liao WT,et al.Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells.Cancer Res,2006;66(12):6225-6232.
7 Yan Y,Wang Y,Zhao P,et al.BMI-1 promotes self-renewal of radio-and temozolomide(TMZ)-resistant breast cancer cells.Reprod Sci,2017;24(12):1620-1629.
8 Moshavash Z,Danyali H,Helfroush MS.An automatic and robust decision support system for accurate acute leukemia diagnosis from blood microscopic images.J Digit Imaging,2018:doi:10.1007/s10278-10018-10074-y.
9 Zhang X,Tian T,Sun W,et al.Bmi-1 overexpression as an efficient prognostic marker in patients with nonsmall cell lung cancer.Medicine(Baltimore),2017;96(26):e7346.
10 Yi C,Li BB,Zhou CX.Bmi-1 expression predicts prognosis in salivary adenoid cystic carcinoma and correlates with epithelialmesenchymal transition-related factors.Ann Diagn Pathol,2016;22:38-44.
11 van Kemenade FJ,Raaphorst FM,Blokzijl T,et al.Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma.Blood,2001;97(12):3896-3901.
12 Chowdhury M,Mihara K,Yasunaga S,et al.Expression of Polycomb-group(PcG)protein BMI-1 predicts prognosis in patients with acute myeloid leukemia.Leukemia,2007;21(5):1116-1122.
13 Osaka M,Koami K,Sugiyama T.Cloning of the rat proto-oncogene bmi-1.Cancer Lett,1998;133(1):57-62.
14 Kajiume T,Ishikawa N,Ohno N,et al.Expression of the polycomb group gene Bmi-1 does not affect the prognosis of pediatric acute lymphoblastic leukemia.Stem Cell Discovery,2012;2(2):25-30.
2 Van Lohuizen M,Verbeek S,Scheijen B,et al.Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging.Cell,1991;65(5):737-752.
3 Park IK,Qian D,Kiel M,et al.Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.Nature,2003;423(6937):302-305.
4 Bruggeman SW,Hulsman D,Tanger E,et al.Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma.Cancer Cell,2007;12(4):328-341.
5 DiMauro T,Cantor DJ,Bainor AJ,et al.Transcriptional repression of Sin3B by Bmi-1 prevents cellular senescence and is relieved by oncogene activation.Oncogene,2015;34(30):4011-4017.
6 Song LB,Zeng MS,Liao WT,et al.Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells.Cancer Res,2006;66(12):6225-6232.
7 Yan Y,Wang Y,Zhao P,et al.BMI-1 promotes self-renewal of radio-and temozolomide(TMZ)-resistant breast cancer cells.Reprod Sci,2017;24(12):1620-1629.
8 Moshavash Z,Danyali H,Helfroush MS.An automatic and robust decision support system for accurate acute leukemia diagnosis from blood microscopic images.J Digit Imaging,2018:doi:10.1007/s10278-10018-10074-y.
9 Zhang X,Tian T,Sun W,et al.Bmi-1 overexpression as an efficient prognostic marker in patients with nonsmall cell lung cancer.Medicine(Baltimore),2017;96(26):e7346.
10 Yi C,Li BB,Zhou CX.Bmi-1 expression predicts prognosis in salivary adenoid cystic carcinoma and correlates with epithelialmesenchymal transition-related factors.Ann Diagn Pathol,2016;22:38-44.
11 van Kemenade FJ,Raaphorst FM,Blokzijl T,et al.Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma.Blood,2001;97(12):3896-3901.
12 Chowdhury M,Mihara K,Yasunaga S,et al.Expression of Polycomb-group(PcG)protein BMI-1 predicts prognosis in patients with acute myeloid leukemia.Leukemia,2007;21(5):1116-1122.
13 Osaka M,Koami K,Sugiyama T.Cloning of the rat proto-oncogene bmi-1.Cancer Lett,1998;133(1):57-62.
14 Kajiume T,Ishikawa N,Ohno N,et al.Expression of the polycomb group gene Bmi-1 does not affect the prognosis of pediatric acute lymphoblastic leukemia.Stem Cell Discovery,2012;2(2):25-30.