成人B细胞性急性淋巴细胞白血病RAG1表达特点及临床意义
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摘要
目的:探讨成人B细胞性急性淋巴细胞白血病(B-ALL)中RAG1基因的表达特点及其临床意义。方法:应用实时定量PCR方法检测104例初发、22例复发成人B-ALL患者和30例正常对照者RAG1基因的表达,分析基因表达特点及其与临床和实验室参数之间的关系。结果:初发、复发成人B-ALL患者RAG1基因表达水平均高于正常对照者(3.94 vs 1.23)(P<0.001);(5.86 vs1.23)(P<0.01)。6例初发与复发患者成对标本分析显示,RAG1表达水平在疾病复发时显著高于初发(13.65 vs2.31)(P<0.01)。IKZF1基因外显子3-6缺失的异构体Ikaros isoform 6(Ik6)阳性患者RAG1基因表达水平显著高于Ik6阴性患者(5.30 vs2.11)(P<0.05)。RAG1高表达组LDH水平大于1 000 U/L患者的比例显著高于低表达组(42.2%vs20.5%)(P<0.05)。结论:RAG1基因表达上调在成人B-ALL发生发展中尤其在复发过程中可能起重要作用,其上调与IKZF1基因缺失相关。监测RAG1表达水平的变化可能为临床预测成人B-ALL患者疾病进展提供帮助。
Objective: RAG1 plays important roles in lymphopoiesis and immune system, its dysfunction may result in the malignancies of hemopoietic system. The aim of this study was to investigate the characteristics of RAG1 expression in adult B-cell acute lymphoblastic leukemia(B-ALL), and to analyze the clinical significances. Methods: Quantitative PCR(q-PCR) was performed to evaluate the expression of RAG1 in 104 newly diagnosed, 22 relapsed adult B-ALL patients and 30 normal controls, the clinical significances of RAG1 expression were analyzed. Results: Compared with normal controls, newly diagnosed and relapsed adult B-ALL patients showed higher RAG1 expression level(3.94 vs 1.23)(P<0.01),(5.86 vs 1.23)(P<0.01). The analysis of paired simples from 6 cases of newly diagnosed and relapsed B-ALL showed that the expression level of RAG1 at relapse was significantly higher than that at new diagnosis(13.65 vs 2.31)(P<0.01). The RAG1 expression level in IK6 positive patients was higher than that in IK6 negative patients(5.30 vs 2.11)(P<0.05). The ratio of patients with LDH>1 000 U/L in RAG1 high expression group was higher than that in RAG1 low expression group(42.2% vs 20.5%)(P<0.05). Conclusion: RAG1 up-regulation may play an important role in the development of adult B-ALL especially when relapsed, which may also take part in the formation of Ik6. Monitoring RAG1 expression may provide a new method to evaluate the prognosis of adult B-ALL patients.
Objective: RAG1 plays important roles in lymphopoiesis and immune system, its dysfunction may result in the malignancies of hemopoietic system. The aim of this study was to investigate the characteristics of RAG1 expression in adult B-cell acute lymphoblastic leukemia(B-ALL), and to analyze the clinical significances. Methods: Quantitative PCR(q-PCR) was performed to evaluate the expression of RAG1 in 104 newly diagnosed, 22 relapsed adult B-ALL patients and 30 normal controls, the clinical significances of RAG1 expression were analyzed. Results: Compared with normal controls, newly diagnosed and relapsed adult B-ALL patients showed higher RAG1 expression level(3.94 vs 1.23)(P<0.01),(5.86 vs 1.23)(P<0.01). The analysis of paired simples from 6 cases of newly diagnosed and relapsed B-ALL showed that the expression level of RAG1 at relapse was significantly higher than that at new diagnosis(13.65 vs 2.31)(P<0.01). The RAG1 expression level in IK6 positive patients was higher than that in IK6 negative patients(5.30 vs 2.11)(P<0.05). The ratio of patients with LDH>1 000 U/L in RAG1 high expression group was higher than that in RAG1 low expression group(42.2% vs 20.5%)(P<0.05). Conclusion: RAG1 up-regulation may play an important role in the development of adult B-ALL especially when relapsed, which may also take part in the formation of Ik6. Monitoring RAG1 expression may provide a new method to evaluate the prognosis of adult B-ALL patients.
引文
1 Li W,Swanson P,Desiderio S.RAG-1 and RAG-2-dependent assembly of functional complexes with V(D)J recombination substrates in solution.Mol Cell Biol,1997;17(12):6932-6939.
2 Oettinger MA,Schatz DG,Gorka C,et al.RAG-1 and RAG-2,adjacent genes that synergistically activate V(D)J recombination.Science,1990;248(4962):1517-1523.
3 Fugmann SD,Lee AI,Shockett PE,et al.The RAG proteins and V(D)J recombination:complexes,ends,and transposition.Annu Rev Immunol,2000;18(1):495-527.
4 Lieber MR,Yu K,Raghavan SC.Roles of nonhomologous DNA end joining,V(D)J recombination,and class switch recombination in chromosomal translocations.DNA Repair(Amst),2006;5(9-10):1234-1245.
5 Notarangelo LD,Kim MS,Walter JE,et al.Human RAG mutations:biochemistry and clinical implications.Nat Rev Immunol,2016;16(4):234-246.
6 Villa A,Sobacchi C,Notarangelo LD,et al.V(D)J recombination defects in lymphocytes due to RAG mutations:severe immunodeficiency with a spectrum of clinical presentations.Blood,2001;97(1):81-88.
7 Mombaerts P,Iacomini J,Johnson RS,et al.RAG-1-deficient mice have no mature B and T lymphocytes.Cell,1992;68(5):869-877.
8 Zhang M,Swanson P.V(D)J recombinase binding and cleavage of cryptic recombination signal sequences identified from lymphoid malignancies.J Biol Chem,2008;283(11):6717-6727.
9 Shimazaki N,Askary A,Swanson PC,et al.Mechanistic basis for RAG discrimination between recombination sites and the Off-target sites of human lymphomas.Mol Cell Biol,2012;32(2):365-375.
10 Papaemmanuil E,Rapado I,Li Y,et al.RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia.Nat Genet,2014;46(2):116-125.
11 Numata M,Saito S,Nagata K.RAG-dependent recombination at cryptic RSSs within TEL-AML1 t(12;21)(p13;q22)chromosomal translocation region.Biochem Bioph Res Co,2010;402(4):718-724.
12郭星,张闰,葛峥,等.FBXW7在成人T细胞性急性淋巴细胞白血病中的突变研究.中国实验血液学杂志,2015;3(23):612-618.
13顾岩,吴雨洁,韩旗,等.成人急性淋巴细胞白血病CRLF2突变特点及其临床意义.中国实验血液学杂志,2017;25(2):328-333.
14 Liu P,Lin Z,Qian S,et al.Expression of dominant-negative Ikaros isoforms and associated genetic alterations in Chinese adult patients with leukemia.Ann Hematol,2012;91(7):1039-1049.
15柳萍,葛峥,林忠琨,等.Ikaros和Helios异构体在白血病中的表达特征及机制的初步研究.中国实验血液学杂志,2012;20(4):812-817.
16 Schatz DG,Swanson PC.V(D)J recombination:mechanisms of initiation.Annu Rev Genet,2011;45(1):167-202.
17 Teng G,Schatz DG.Regulation and evolution of the RAGrecombinase.Adv Immunol,2015;128:1-39.
18 Mijuskovic M,Chou YF,Gigi V,et al.Off-target V(D)Jrecombination drives lymphomagenesis and is escalated by loss of the Rag2 C terminus.Cell Rep,2015;12(11):1842-1852.
19 Knecht H,Joske DJ,Bachmann E,et al.Expression of human recombination activating genes(RAG-1 and RAG-2)in angioimmunoblastic lymphadenopathy and anaplastic large cell lymphoma of T-type.Brit J Haematol,1993;83(4):655-659.
20 Swaminathan S,Klemm L,Park E,et al.Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia.Nat immunol,2015;16(7):766-774.
21 Ge Z,Gu Y,Zhao G,et al.High CRLF2 expression associates with IKZF1 dysfunction in adult acute lymphoblastic leukemia without CRLF2 rearrangement.Oncotarget,2016;7(31):49722-49732.
22 Ge Z,Gu Y,Xiao L,et al.Co-existence of IL7R high and SH2B3low expression distinguishes a novel high-risk acute lymphoblastic leukemia with Ikaros dysfunction.Oncotarget,2016;7(29):46014-46027.
2 Oettinger MA,Schatz DG,Gorka C,et al.RAG-1 and RAG-2,adjacent genes that synergistically activate V(D)J recombination.Science,1990;248(4962):1517-1523.
3 Fugmann SD,Lee AI,Shockett PE,et al.The RAG proteins and V(D)J recombination:complexes,ends,and transposition.Annu Rev Immunol,2000;18(1):495-527.
4 Lieber MR,Yu K,Raghavan SC.Roles of nonhomologous DNA end joining,V(D)J recombination,and class switch recombination in chromosomal translocations.DNA Repair(Amst),2006;5(9-10):1234-1245.
5 Notarangelo LD,Kim MS,Walter JE,et al.Human RAG mutations:biochemistry and clinical implications.Nat Rev Immunol,2016;16(4):234-246.
6 Villa A,Sobacchi C,Notarangelo LD,et al.V(D)J recombination defects in lymphocytes due to RAG mutations:severe immunodeficiency with a spectrum of clinical presentations.Blood,2001;97(1):81-88.
7 Mombaerts P,Iacomini J,Johnson RS,et al.RAG-1-deficient mice have no mature B and T lymphocytes.Cell,1992;68(5):869-877.
8 Zhang M,Swanson P.V(D)J recombinase binding and cleavage of cryptic recombination signal sequences identified from lymphoid malignancies.J Biol Chem,2008;283(11):6717-6727.
9 Shimazaki N,Askary A,Swanson PC,et al.Mechanistic basis for RAG discrimination between recombination sites and the Off-target sites of human lymphomas.Mol Cell Biol,2012;32(2):365-375.
10 Papaemmanuil E,Rapado I,Li Y,et al.RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia.Nat Genet,2014;46(2):116-125.
11 Numata M,Saito S,Nagata K.RAG-dependent recombination at cryptic RSSs within TEL-AML1 t(12;21)(p13;q22)chromosomal translocation region.Biochem Bioph Res Co,2010;402(4):718-724.
12郭星,张闰,葛峥,等.FBXW7在成人T细胞性急性淋巴细胞白血病中的突变研究.中国实验血液学杂志,2015;3(23):612-618.
13顾岩,吴雨洁,韩旗,等.成人急性淋巴细胞白血病CRLF2突变特点及其临床意义.中国实验血液学杂志,2017;25(2):328-333.
14 Liu P,Lin Z,Qian S,et al.Expression of dominant-negative Ikaros isoforms and associated genetic alterations in Chinese adult patients with leukemia.Ann Hematol,2012;91(7):1039-1049.
15柳萍,葛峥,林忠琨,等.Ikaros和Helios异构体在白血病中的表达特征及机制的初步研究.中国实验血液学杂志,2012;20(4):812-817.
16 Schatz DG,Swanson PC.V(D)J recombination:mechanisms of initiation.Annu Rev Genet,2011;45(1):167-202.
17 Teng G,Schatz DG.Regulation and evolution of the RAGrecombinase.Adv Immunol,2015;128:1-39.
18 Mijuskovic M,Chou YF,Gigi V,et al.Off-target V(D)Jrecombination drives lymphomagenesis and is escalated by loss of the Rag2 C terminus.Cell Rep,2015;12(11):1842-1852.
19 Knecht H,Joske DJ,Bachmann E,et al.Expression of human recombination activating genes(RAG-1 and RAG-2)in angioimmunoblastic lymphadenopathy and anaplastic large cell lymphoma of T-type.Brit J Haematol,1993;83(4):655-659.
20 Swaminathan S,Klemm L,Park E,et al.Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia.Nat immunol,2015;16(7):766-774.
21 Ge Z,Gu Y,Zhao G,et al.High CRLF2 expression associates with IKZF1 dysfunction in adult acute lymphoblastic leukemia without CRLF2 rearrangement.Oncotarget,2016;7(31):49722-49732.
22 Ge Z,Gu Y,Xiao L,et al.Co-existence of IL7R high and SH2B3low expression distinguishes a novel high-risk acute lymphoblastic leukemia with Ikaros dysfunction.Oncotarget,2016;7(29):46014-46027.