慢性髓系白血病患者中基因SCIN表达及启动子甲基化的临床研究
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摘要
目的:探讨基因SCIN表达及启动子甲基化在慢性髓系白血病(CML)患者中的临床意义。方法:应用实时定量PCR检测64例CML患者和37例对照骨髓单个核细胞SCIN的表达水平。应用实时定量甲基化特异性PCR结合亚硫酸盐测序PCR检测65例CML患者和29例对照SCIN启动子甲基化水平。结果:CML患者与对照组相比细胞SCIN表达水平明显下调(P=0.010);慢性期、加速期与急变期患者中SCIN表达下调率分别为61%、67%和75%,有增加趋势。Spearman相关性分析显示,基因SCIN表达与BCR-ABL1转录水平呈负相关(r=-0.315,P<0.05)。然而,SCIN低表达组与高表达组相比较,在性别、年龄、外周血白细胞数、血红蛋白水平、血小板数量、染色体特征、CML分期及BCR-ABL1转录水平等临床参数中未见差异(P>0.05)。CML患者SCIN启动子甲基化水平与对照组比较无统计学差异,且SCIN表达与启动子甲基化水平无相关性(P>0.05)。结论:基因SCIN在CML患者中非甲基化依赖性表达下调,可能与BCR-ABL1融合基因致病CML有关;SCIN表达下调可能与CML进展有关。
Objective: To investigate the clinical significance of SCIN gene expression and promoter methylation in patients with chronic myeloid leukemia(CML). Methods: Real-time quantitative PCR was used to detect the expression level of SCIN in mononucleatr cells of bone marrow samples from nts with CML and 64 CML patients and 37 controls. The methylation levels of SCIN promoter in 65 patiesults: T2 h9 controls were detected by real-time quantitative methylationspecific PCR and bisulfite sequencing PCR. Ree expression level of SCIN in CML patients was significantly down-regulated(P<0.05), compared with the control group. The down-regulation rate of SCIN expression in CML patients at chronic phase, accelerated phase and blast crisis was 61%, 67% and 75%, respectively. Spearman correlation analysis showed that the expression level of SCIN negatively correlated with the transcript level of BCR-ABL1(R=-0.315, P<0.05). However, there was no significant difference in clinical parameters such as sex, age, white blood cell count, hemoglobin level, platelet count, chromosome, CML staging and BCL-ABL1 transcript level between low and high SCIN expression groups of CML patients(P>0.05). No significant difference in methylation of SCIN promoter between CML patients and controls, and no correlation between SCIN expression and promoter methylation were observed(P >0.05). Conclusion: The SCIN expression is down-regulated in CML patients, which may relate with the pathogenesis that is, BCR-ABL1 fusion gene induces CML tumorigenesis. The down-regulation of SCIN expression may relate with the progression of CML.
Objective: To investigate the clinical significance of SCIN gene expression and promoter methylation in patients with chronic myeloid leukemia(CML). Methods: Real-time quantitative PCR was used to detect the expression level of SCIN in mononucleatr cells of bone marrow samples from nts with CML and 64 CML patients and 37 controls. The methylation levels of SCIN promoter in 65 patiesults: T2 h9 controls were detected by real-time quantitative methylationspecific PCR and bisulfite sequencing PCR. Ree expression level of SCIN in CML patients was significantly down-regulated(P<0.05), compared with the control group. The down-regulation rate of SCIN expression in CML patients at chronic phase, accelerated phase and blast crisis was 61%, 67% and 75%, respectively. Spearman correlation analysis showed that the expression level of SCIN negatively correlated with the transcript level of BCR-ABL1(R=-0.315, P<0.05). However, there was no significant difference in clinical parameters such as sex, age, white blood cell count, hemoglobin level, platelet count, chromosome, CML staging and BCL-ABL1 transcript level between low and high SCIN expression groups of CML patients(P>0.05). No significant difference in methylation of SCIN promoter between CML patients and controls, and no correlation between SCIN expression and promoter methylation were observed(P >0.05). Conclusion: The SCIN expression is down-regulated in CML patients, which may relate with the pathogenesis that is, BCR-ABL1 fusion gene induces CML tumorigenesis. The down-regulation of SCIN expression may relate with the progression of CML.
引文
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6 Ben Hassine I,Gharbi H,Soltani I,et al.Molecular study of ABCB1gene and its correlation with imatinib response in chronic myeloid leukemia.Cancer Chemoth Pharm,2017;80(4):829-839.
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8 Song MK,Lee ZH,Kim HH.Adseverin mediates RANKL-induced osteoclastogenesis by regulating NFATc1.Exp Mol Med,2015;47:e199.
9 Kwiatkowski DJ.Functions of gelsolin:motility,signaling,apoptosis,cancer.Curr Opin Cell Biol,1999;11(1):103-108.
10 Liu JJ,Liu JY,Chen J,et al.Scinderin promotes the invasion and metastasis of gastric cancer cells and predicts the outcome of patients.Cancer Lett,2016;376(1):110-117.
11 Liu HX,Shi DW,Liu TQ,et al.Lentivirus-mediated silencing of SCIN inhibits proliferation of human lung carcinoma cells.Gene,2015;554(1):32-39.
12 Swerdlow SH,Campo E,Harris NL,et al.WHO classification of tumours of haematopoietic and lymphoid tissues.4th ed.,Lyon France:IARC Press,2008:1-493.
13 Zhang TJ,Zhou JD,Ma JC,et al.CDH1(E-cadherin)expression independently affects clinical outcome in acute myeloid leukemia with normal cytogenetics.Clin Chem Lab Med,2017;55(1):123-131.
14 Kim H,Gillis LC,Jarvis JD,et al.Tyrosine kinase chromosomal translocations mediate distinct and overlapping gene regulation events.BMC Cancer,2011;11:528.
15 Druker BJ,Talpaz M,Resta DJ,et al.Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.N Engl J Med,2001;344(14):1031-1037.
16 Dawson MA,Kouzarides T.Cancer epigenetics:from mechanism to therapy.Cell,2012;150(1):12-27.
17 Wouters BJ,Delwel R.Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia.Blood,2016;127(1):42-52.
2 Hughes T,Branford S.Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukemia.Blood Rev,2006;20(1):29-41.
3 Apperley JF.Chronic myeloid leukemia.Lancet,2015;385(9976):1447-1459.
4 Zhou JD,Lin J,Zhang TJ,et al.Hypomethylation-mediated H19overexpression increases the risk of disease evolution through the association with BCR-ABL transcript in chronic myeloid leukemia.J Cell Physiol,2018;233(3):2444-2450.
5 Roman-Gomez J,Jimenez-Velasco A,Agirre X,et al.Epigenetic regulation of PRAME gene in chronic myeloid leukemia.Leuk Res,2007;31(11):1521-1528.
6 Ben Hassine I,Gharbi H,Soltani I,et al.Molecular study of ABCB1gene and its correlation with imatinib response in chronic myeloid leukemia.Cancer Chemoth Pharm,2017;80(4):829-839.
7 Zunino R,Li Q,Rose SD,et al.Expression of scinderin in megakaryoblastic leukemia cells induces differentiation,maturation,andapoptosis with release of platelet like particles and inhibits proliferation and tumorigenesis.Blood,2001;98(7):2210-2219.
8 Song MK,Lee ZH,Kim HH.Adseverin mediates RANKL-induced osteoclastogenesis by regulating NFATc1.Exp Mol Med,2015;47:e199.
9 Kwiatkowski DJ.Functions of gelsolin:motility,signaling,apoptosis,cancer.Curr Opin Cell Biol,1999;11(1):103-108.
10 Liu JJ,Liu JY,Chen J,et al.Scinderin promotes the invasion and metastasis of gastric cancer cells and predicts the outcome of patients.Cancer Lett,2016;376(1):110-117.
11 Liu HX,Shi DW,Liu TQ,et al.Lentivirus-mediated silencing of SCIN inhibits proliferation of human lung carcinoma cells.Gene,2015;554(1):32-39.
12 Swerdlow SH,Campo E,Harris NL,et al.WHO classification of tumours of haematopoietic and lymphoid tissues.4th ed.,Lyon France:IARC Press,2008:1-493.
13 Zhang TJ,Zhou JD,Ma JC,et al.CDH1(E-cadherin)expression independently affects clinical outcome in acute myeloid leukemia with normal cytogenetics.Clin Chem Lab Med,2017;55(1):123-131.
14 Kim H,Gillis LC,Jarvis JD,et al.Tyrosine kinase chromosomal translocations mediate distinct and overlapping gene regulation events.BMC Cancer,2011;11:528.
15 Druker BJ,Talpaz M,Resta DJ,et al.Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.N Engl J Med,2001;344(14):1031-1037.
16 Dawson MA,Kouzarides T.Cancer epigenetics:from mechanism to therapy.Cell,2012;150(1):12-27.
17 Wouters BJ,Delwel R.Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia.Blood,2016;127(1):42-52.