成人急性淋巴细胞白血病预后分子标记IL7R和JAK3特征研究

发布时间：2018-06-15 00:48

本文选题：IL7R + 急性淋巴细胞白血病　；参考：《南京医科大学》2016年硕士论文

【摘要】：第一部分 IL7R在成人急性淋巴细胞白血病中的突变、表达及其临床意义目的：IL-7R (interleukin-7 receptor)是IL-7的受体。IL-7R由IL-7Ra(由IL7R编码)和γc组成。本研究旨在探讨成人急性淋巴细胞白血病(adult acute Lymphoblastic Leukemia, ALL)中IL7R突变与IL7R的表达特征及其临床意义。方法：本研究通过对成人ALL患者(144例)IL7R外显子(exon) 2-8进行扩增、克隆和测序,研究IL7R突变的发生率、突变位点和类型。通过实时荧光定量PCR检测ALL患者IL 7R mRNA表达水平。分析IL7R突变及表达异常与NOTCH1、PHF6突变的相关性及其预后意义。统计学分析采用SPSS20.0软件,白细胞计数(white blood cell,WBC)、骨髓(bone marrow,BM)原始细胞数、外周血(peripheral blood,PB)原始细胞数等计量资料的差异采用非参数Mann-Whitney检验；计数资料采用χ2检验(或Fisher精确检验)进行差异性分析；Kalplan-Meier检验方法分析生存曲线。P0.05认为结果具有统计学意义。结果：本组成人ALL患者中IL7R的突变率为2.8%,均为缺失或插入突变(为外显子5和6)；本组研究中观察到5种SNP(Single Nucleotide Polymorphisms)改变,分别位于exon2(rs1494558),exon4(rs1494555、rs2228141)和exon8 (rs3194051、rs2229232);同时,本研究还观察到IL7R突变与NOTCH1和/或PHF6突变共存。T-ALL患者中IL7R低表达组的无进展生存(progression free survival,PFS)时间长于高表达组(P=0.036)。结论：T-ALL患者中IL7RmRNA高表达组PFS更短,IL7R表达水平在成人T-ALL患者中可能具有预后价值。第二部分 JAK3在成人T细胞性急性淋巴细胞白血病中的突变研究目的：JAK3是JAKs (Janus Kinase)家族成员之一,在介导细胞因子受体胞内信号中扮演重要角色。在多种造血系统肿瘤中已发现JAK3功能异常。本文目的在于研究成人T细胞性急性淋巴细胞白血病(T-cell acute lymphoblastic leukemia, T-ALL)中JAK3基因突变。方法：本研究通过对成人ALL患者JAK3外显子(exon) 6、11、12、15、19进行扩增和测序,研究JAK3突变发生率,突变位点和类型、与IL7R/JAK突变的相关性及其预后意义。统计学分析采用SPSS20.0软件,白细胞计数(white blood cell,WBC).骨髓(bone marrow, BM)原始细胞数、外周血(peripheral blood,PB)原始细胞数等计量资料的差异采用非参数Mann-Whitney检验；计数资料采用χ2检验(或Fisher精确检验)进行差异性分析；Kalplan-Meier检验方法分析生存曲线。P0.05认为结果具有统计学意义。结果：本研究只在成人T-ALL (39例)发现JAK3突变,突变率为12.8%(5/39),共发现3种点突变(M511I,Y886终止,R887H)；同时,本组研究观察到1例JAK3突变与IL7R突变共存,未发现与JAK1突变共存；T-ALL患者中IL7RIJAK信号通路突变组中位年龄大于无突变组(38.4岁vs.27.9岁,P=0.017), IL7RIJAK信号通路突变组CD8阳性率明显低于无突变组(273%vs.70.4%,P=0.019)。结论：IL7R/JAK信号通路突变在成人T-ALL发病机制中有重要作用。
[Abstract]:Part I mutation, expression and Clinical significance of IL-7R in Adult Acute Lymphocytic Leukemia objective: IL-7R is the receptor of IL-7. IL-7R is composed of IL-7Raand 纬 c. The purpose of this study was to investigate the expression of IL-7R mutation and IL-7R in adult acute of adult patients with acute lymphoblastic leukemia (ALLL) and its clinical significance. Methods: in this study, the incidence, mutation site and type of IL-7R mutation were studied by amplification, cloning and sequencing of exon 2-8 from 144 adult all patients. The expression of IL 7 R mRNA in all patients was detected by real time fluorescent quantitative PCR. To analyze the relationship between IL-7R mutation and abnormal expression of IL-7R and NOTCH1 / PHF6 mutation and its prognostic significance. Statistical analysis was performed with SPSS 20.0 software. The difference of the number of white blood cell (WBC) and the number of PBs in peripheral blood were measured by non-parametric Mann-Whitney test. 蠂 2 test (or Fisher accurate test) was used to analyze the difference of the counting data. The survival curve was analyzed by Kalplan-Meier test. The result was statistically significant. Results: the mutation rate of IL 7R in adult all patients was 2.8, which was deletion or insertion mutation (exon 5 and 6). The changes of 5 SNPs single Nucleotide Polymorphismswere observed in exon2rs1494558exon4rs149455rs2228141 and exon8 rs3194051rs2229232, respectively. It was also observed that the time of progressive free survival PFSs in IL-7R and NOTCH1 and / or PHF6 low expression group was longer than that in high expression group. Conclusion the expression of IL-7R in the high expression of IL-7R mRNA in patients with T-ALL may have prognostic value in adult T-ALL patients. Part two the mutation of JAK3 in adult T cell acute lymphoblastic leukemia objective: JAK3 is a member of the Janus Kinase family and plays an important role in mediating intracellular signal of cytokine receptor. Abnormal JAK3 function has been found in various hematopoietic system tumors. The aim of this study was to study the mutation of JAK3 gene in T-cell acute lymphoblastic leukemia, T-ALL of adult T cell acute lymphoblastic leukemia. Methods: in this study, we amplified and sequenced the JAK3 exon 61112A151519 in adult all patients, and studied the incidence, mutation site and type of JAK3 mutation, the relationship between JAK3 mutation and IL-7RJAK mutation and its prognostic significance. SPSS 20.0 software was used to analyze the white blood cell count. The difference of bone marrow (BMN) primordial cells and peripheral blood PBs was measured by non-parametric Mann-Whitney test, and the difference was analyzed by 蠂 2 test (or Fisher accurate test). Kalplan-Meier test analysis of survival curve. P05 that the results were statistically significant. Results: in this study, only 39 adults (T-ALL) found JAK3 mutation with a mutation rate of 12.80.Three point mutations (M511IY886) were found to terminate R887H1.At the same time, one case of JAK3 mutation coexisted with IL7R mutation, but not with JAK1 mutation. In T-ALL patients, the median age of IL-7RIJAK signal pathway mutation group was larger than that of non-mutation group. The CD8 positive rate of IL-7RIJAK signal pathway mutation group was significantly lower than that of non-mutation group. Conclusion the mutation of IL 7 R / JAK signaling pathway may play an important role in the pathogenesis of adult T-ALL.
【学位授予单位】：南京医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R733.71

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