异基因造血干细胞移植治疗难治复发急性髓细胞白血病的临床及实验研究
发布时间：2018-09-19 11:47
【摘要】：【目的】1.回顾总结本中心应用异基因造血干细胞移植(allo-HSCT)治疗的难治复发急性髓细胞白血病(r AML)患者,研究影响预后的关键因素。2.应用高通量二代测序技术检测初诊及接受allo-HSCT后复发的r AML患者的肿瘤相关基因突变和克隆演变。3.研究Notch2基因在AML中的表达水平及可能的致白血病机制。【方法】1.回顾性收集101例于2003年10月至2012年12月期间,在苏州大学附属第一医院接受allo-HSCT的r AML患者,分析其年龄、FAB分型、分子/细胞遗传学、疾病状态、体能状态、化疗次数、移植类型等临床特征与移植后并发症及预后的影响。2.收集23例原发性r AML初诊标本和20例AML患者(12例AML及8例r AML)初诊及allo-HSCT后复发时的成对样本,应用DNA+RNA特异性基因Panel对390个肿瘤相关基因进行DNA测序(全部外显子及相关内含子)及全转录组测序(RNA-seq)。DNA平均测序深度为300×,RNA-seq测序深度为50M reads。分析r AML患者初诊时基因突变特征及移植后复发时的克隆演变。3.采用实时荧光定量PCR技术检测我中心52例初诊成人AML患者、10例急性淋巴细胞白血病(ALL)及10例健康对照的Notch2基因m RNA表达水平。比较Notch2基因m RNA表达水平在AML患者和ALL患者及正常对照之间以及AML各亚组之间的差异。分析Notch2 m RNA表达量与无病生存率(DFS)和总生存率(OS)之间的关系。同时制备Notch2过表达载体及靶向抑制Notch2的sh RNA质粒载体,分别转染髓系白血病细胞株THP-1,采用绝对计数等方法检测其对细胞生长的影响。【结果】1.101例接受allo-HSCT的r AML患者临床特征与预后的研究101例r AML患者中位年龄34岁(14-58),所有患者均接受清髓性移植。移植方式情况如下:1)38例HLA全相合同胞移植,2)33例HLA相合无关供体移植,3)30例HLA不全相合的亲缘移植。53例患者(52%)在移植前疾病缓解(CR组),而48例患者未缓解(NR组)。与CR组患者相比,NR组有更多患者存在FLT3-ITD突变(P=0.006),且体能状态更差(P=0.001),有更多患者行无关供体移植(P=0.027),更少例数接受再诱导化疗(P=0.002)。CR组患者5年OS为46%,而NR组为18%,两组5年累计复发率分别为45%和81%。然而,两组5年NRM是相似的(分别为28%和30%)。CR患者中,32例移植前MRD检测阳性(MRDpos),21例MRD阴性(MRDneg)。两组患者年龄、性别、FAB分型、危险分层及体能状态分布相似。MRDneg患者和MRDpos患者的5年预期OS分别为51%和41%(P=0.37),5年预期DFS分别为55%和36%(P=0.20),5年预期RI分别为21%和29%(P=0.43)。所有患者单因素分析发现,非M5/M6型AML,低危组细胞遗传学和分子遗传学、移植时CR状态以及移植前较好的体能状态与生存率正相关。多因素分析发现,与较好预后相关的因素是移植前CR状态(风险比[HR]=0.31,95%CI 0.12-0.81,P=0.017)和较好的体能状态评分(Zubrod-ECOG-WHO3)。CR组患者单因素分析提示,非M5/M6型AML、低危组细胞遗传学和分子遗传学、FLT3-ITD突变阴性、良好的体能状态和化疗疗程数量≤4次与患者的生存率正相关。多因素分析发现三个独立的预后因素与较长的生存时间相关,分别是较好的体能状态(Zubrod-ECOG-WHO3)(HR=0.13,95%CI 0.045-0.391,P0.001)、细胞遗传学低/中危组(HR=0.30,95%CI0.103-0.853,P=0.026)和无FLT3/ITD突变(HR=0.22,95%CI 0.058-0.831,P=0.024)。2.allo-HSCT治疗r AML后复发克隆演变的初步研究(1)r AML患者初诊时基因突变特征23名r AML患者初诊时每个样本检出基因异常的中位数为4个(2-15)。出现频率最高的基因异常为FLT3突变。其次为TET2突变和MLL融合基因。生存分析发现,携带FLT3突变及MLL融合基因患者似乎预后更差,应用FLT3抑制剂能提高FLT3-ITD患者诱导缓解率,改善预后(2年OS 33%vs.75%)。(2)AML患者初诊及移植后复发时的基因改变20位AML患者初诊时最常见的四种基因突变为FLT3、DNMT3A、CEBPA和NPM1。涉及信号通路和表观遗传调控的基因突变最为多见。8名难治复发患者最常见的基因突变为FLT3和TET2。移植后首次复发时,出现突变频率较高的基因为MSH3、KMT2C、TSC2、WT1和NOTCH2。涉及表观遗传学及抑癌基因的基因突变最为多见。难治复发患者中,TSC2、TNFAIP3、IGF1R、WT1出现率最高。其中,Notch2基因突变只发生于移植后复发时,初诊时并未发现,且4例患者中有3名为难治复发患者。(3)移植后复发时克隆的演变移植后复发时克隆演变三种模式:(1)移植后复发时的基因突变与初诊时检测的基因突变无一相同,即复发时出现一群新的克隆。(2)移植后复发时,在初诊基因异常的基础上获得了新的基因异常。(3)在移植后复发时缺失了1个或多个基因异常,同时又获得了1个或多个基因异常。3.Notch2在成人AML患者中的表达、意义及其功能的初步探讨(1)AML患者中Notch2基因m RNA的表达水平AML患者中Notch2基因m RNA的表达水平高于正常对照组(P0.05)及ALL组(P=0.180)。根据FAB分型分组发现,M3患者的Notch2基因m RNA的相对表达量为0.07494,而其他组表达量中位值0.04637(P=0.174)。根据染色体核型分组发现,伴有t(15,17)核型组和伴有11q23/MLL组的Notch2表达量分别为0.07494和0.06200,其他核型组表达量中位值为0.04762(P=0.22)。(2)Notch2 m RNA表达量与预后的关系Kaplan-Meier分析发现,正常核型AML患者中Notch2基因m RNA高表达组(相对表达量≥0.04)的2年DFS高于低表达组(相对表达量0.04)(2年DFS分别为51%和17%,P=0.047)。而低表达组和高表达组患者的2年OS差异不显著,分别为38%和63%(P=0.528)。在其他中危核型患者中,Notch2基因m RNA表达量与预后无显著关联(P0.05)。(3)过表达Notch2能使白血病细胞株THP-1的生长和集落形成能力下降,但是沉默该基因的表达,对其生长增殖未造成显著影响。【结论】1.处于缓解期和体能状态较好的r AML患者在allo-HSCT后,能取得更好的预后。对于移植前处于缓解状态的r AML患者,细胞/分子遗传学以及体能状态对移植结果有显著影响。2.AML患者初诊和异基因造血干细胞移植后复发时,推测基因突变类型可能发生了3种演变模式。初诊时多见涉及信号通路及DNA甲基化调控的基因突变,复发时新出现的基因异常却多见于染色质修饰基因和抑癌基因。3.AML患者中均表达Notch2,在正常核型患者中用荧光实时定量检测Notch2基因m RNA表达水平有一定的提示预后的价值。过表达Notch2在一定程度上能抑制白血病细胞株THP-1增殖,而沉默该基因对细胞株生长影响不显著。
[Abstract]:[Objective] 1. Retrospective study of the key prognostic factors in patients with refractory and relapsed acute myeloid leukemia (r AML) treated with allo-HSCT in our center. 2. Detection of tumor-related gene mutations and cloning in patients with newly diagnosed and relapsed R AML after allo-HSCT by high-throughput second-generation sequencing technique. Evolution. 3. To study the expression of Notch2 gene in AML and its possible leukemic mechanism. [Methods] 1. A retrospective study of 101 patients with allo-HSCT treated in the First Affiliated Hospital of Suzhou University from October 2003 to December 2012 was conducted to analyze their age, FAB typing, molecular/cytogenetics, disease status, physical status, and chemotherapy. Clinical features such as frequency, type of transplantation, and their impact on post-transplant complications and prognosis. 2. DNA sequencing of 390 tumor-related genes (all exons and related genes) was performed in 23 primary r-AML patients and 20 AML patients (12 AML and 8 r-AML) with paired samples at initial diagnosis and relapse after allo-HSCT. Intron) and total transcriptome sequencing (RNA-seq). The average DNA sequencing depth was 300 * and the RNA-seq sequencing depth was 50 M reads. The gene mutation characteristics at the initial diagnosis and the clonal evolution during the relapse after transplantation were analyzed. 3. Real-time fluorescence quantitative PCR was used to detect 52 newly diagnosed adult AML patients and 10 acute lymphoblastic leukemia (ALL) patients in our center. The expression level of Notch2 m RNA was compared between AML patients and ALL patients, as well as between AML subgroups. The relationship between Notch2 m RNA expression and disease-free survival rate (DFS) and overall survival rate (OS) was analyzed. Notch2 overexpression vector and targeted inhibition were prepared. Notch2 plasmid was transfected into myeloid leukemia cell line THP-1 and its effect on cell growth was detected by absolute count. [Results] The clinical characteristics and prognosis of 101 patients with allo-HSCT-induced AML were studied. The median age of 101 patients with allo-HSCT-induced AML was 34 years (14-58). All patients received myeloablative transplantation. The methods were as follows: 1) 38 HLA full-phase contract cell transplantation, 2) 33 HLA-matched unrelated donor transplantation, 3) 30 HLA-incompatible relative transplantation. 53 patients (52%) had remission before transplantation (CR group), while 48 patients had no remission (NR group). Compared with CR group, more patients in NR group had FLT3-ITD mutation (P = 0.006) and worse physical condition (P = 0.006). More patients received unrelated donor transplantation (P = 0.027) and fewer received re-induction chemotherapy (P = 0.002). The 5-year OS was 46% in CR group and 18% in NR group. The cumulative 5-year recurrence rate was 45% and 81% in NR group, respectively. However, the 5-year NRM of the two groups was similar (28% and 30% respectively). Age, sex, FAB typing, risk stratification, and physical fitness distribution were similar in both groups. The 5-year expected OS of MRDneg patients and MDRPOS patients were 51% and 41% (P = 0.37), 55% and 36% (P = 0.20), and 29% (P = 0.43) respectively. Univariate analysis of all patients revealed that non-M5/M6 AML was inherited by low-risk group cells. Multivariate analysis showed that CR status before transplantation (risk ratio [HR] = 0.31, 95% CI 0.12-0.81, P = 0.017) and better physical fitness status score (Zubrod-ECOG-WHO 3) were associated with better prognosis. 5/M6 AML, low-risk group cytogenetics and molecular genetics, FLT3-ITD mutation negative, good physical fitness status and the number of chemotherapy courses less than 4 times were positively correlated with the survival rate of patients. Multivariate analysis found that three independent prognostic factors were associated with longer survival time (Zubrod-ECOG-WHO 3) (HR = 0.13, 95% CI 0. 045-0.391, P 0.001), cytogenetic low/intermediate risk group (HR = 0.30, 95% CI0.103-0.853, P = 0.026) and non-FLT3/ITD mutation (HR = 0.22, 95% CI 0.058-0.831, P = 0.024). 2. Preliminary study on clonal evolution of relapse cloning after treatment of AML with allo-HSCT (1) Characteristics of gene mutation in 23 patients with AML at first diagnosis The highest frequency of gene abnormalities was FLT3 mutation, followed by TET2 mutation and MLL fusion gene. Survival analysis showed that patients with FLT3 mutation and MLL fusion gene seemed to have worse prognosis. FLT3 inhibitors could increase the induced remission rate and improve the prognosis of FLT3-ITD patients (33% vs. 75% in 2 years OS) after initial diagnosis and transplantation. The most common four mutations were FLT3, DNMT3A, CEBPA and NPM1. The most common mutations involved in signal pathway and epigenetic regulation were FLT3 and TET2. MSH3 was the most frequent mutation in the first relapse after transplantation. KMT2C, TSC2, WT1 and NOTCH2. Epigenetics and tumor suppressor gene mutations were the most common. TSC2, TNFAIP3, IGF1R and WT1 were the most common in refractory recurrence patients. Notch2 gene mutations occurred only in the recurrence after transplantation, and were not found at first diagnosis. Three of the four patients were cloned in the recurrence after transplantation. Three patterns of clonal evolution during post-transplant recurrence were observed: (1) There was no difference in gene mutation between post-transplant recurrence and initial diagnosis, i.e. a group of new clones appeared during recurrence. (2) New gene abnormalities were acquired on the basis of initial diagnosis of gene abnormalities during post-transplant recurrence. (3) One or more gene abnormalities were missing during post-transplant recurrence. The expression and function of Notch2 gene in adult AML patients (1) The expression level of Notch2 gene m RNA in AML patients was higher than that in normal control group (P 0.05) and ALL group (P = 0.180). According to FAB classification, the expression of Notch2 gene m RNA in AML patients was higher than that in normal control group (P 0.05) and ALL group (P = 0.180). The relative expression of Notch2 m RNA was 0.07494 in 3 patients and 0.04637 in other groups (P = 0.174). According to the karyotype grouping, the expression of Notch2 in the group with t (15,17) karyotype and the group with 11q23/MLL were 0.07494 and 0.06200, respectively. The median expression of Notch2 m RNA in other karyotypes was 0.04762 (P = 0.22). Kaplan-Meier analysis showed that the 2-year DFS in the high-expression group of Notch2 gene m RNA (relative expression (>0.04)) was higher than that in the low-expression group (relative expression 0.04) (2-year DFS was 51% and 17%, respectively, P = 0.047). The 2-year OS in the low-expression group and the high-expression group were not significantly different, 38% and 63% (P = 0.528), respectively. There was no significant correlation between the expression of Notch2 gene m RNA and prognosis in other patients with intermediate-risk karyotypes (P 0.05). (3) Overexpression of Notch2 could decrease the growth and colony-forming ability of leukemia cell line THP-1, but silencing the expression of Notch2 gene had no significant effect on its growth and proliferation. [Conclusion]1. AML patients have a better prognosis after allo-HSCT. Cell/molecular genetics and physical fitness status have a significant impact on transplantation outcomes in patients with remission before transplantation. 2. When AML patients first diagnosed and relapsed after allogeneic hematopoietic stem cell transplantation, three patterns of gene mutation may occur. Mutations involving signaling pathways and DNA methylation regulation are common, but new gene abnormalities occurring during relapse are more common in chromatin modified genes and tumor suppressor genes. CH2 can inhibit the proliferation of leukemia cell line THP-1 to some extent, but the silencing of this gene has no significant effect on the growth of leukemia cell line.
【学位授予单位】：苏州大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R733.71
[Abstract]:[Objective] 1. Retrospective study of the key prognostic factors in patients with refractory and relapsed acute myeloid leukemia (r AML) treated with allo-HSCT in our center. 2. Detection of tumor-related gene mutations and cloning in patients with newly diagnosed and relapsed R AML after allo-HSCT by high-throughput second-generation sequencing technique. Evolution. 3. To study the expression of Notch2 gene in AML and its possible leukemic mechanism. [Methods] 1. A retrospective study of 101 patients with allo-HSCT treated in the First Affiliated Hospital of Suzhou University from October 2003 to December 2012 was conducted to analyze their age, FAB typing, molecular/cytogenetics, disease status, physical status, and chemotherapy. Clinical features such as frequency, type of transplantation, and their impact on post-transplant complications and prognosis. 2. DNA sequencing of 390 tumor-related genes (all exons and related genes) was performed in 23 primary r-AML patients and 20 AML patients (12 AML and 8 r-AML) with paired samples at initial diagnosis and relapse after allo-HSCT. Intron) and total transcriptome sequencing (RNA-seq). The average DNA sequencing depth was 300 * and the RNA-seq sequencing depth was 50 M reads. The gene mutation characteristics at the initial diagnosis and the clonal evolution during the relapse after transplantation were analyzed. 3. Real-time fluorescence quantitative PCR was used to detect 52 newly diagnosed adult AML patients and 10 acute lymphoblastic leukemia (ALL) patients in our center. The expression level of Notch2 m RNA was compared between AML patients and ALL patients, as well as between AML subgroups. The relationship between Notch2 m RNA expression and disease-free survival rate (DFS) and overall survival rate (OS) was analyzed. Notch2 overexpression vector and targeted inhibition were prepared. Notch2 plasmid was transfected into myeloid leukemia cell line THP-1 and its effect on cell growth was detected by absolute count. [Results] The clinical characteristics and prognosis of 101 patients with allo-HSCT-induced AML were studied. The median age of 101 patients with allo-HSCT-induced AML was 34 years (14-58). All patients received myeloablative transplantation. The methods were as follows: 1) 38 HLA full-phase contract cell transplantation, 2) 33 HLA-matched unrelated donor transplantation, 3) 30 HLA-incompatible relative transplantation. 53 patients (52%) had remission before transplantation (CR group), while 48 patients had no remission (NR group). Compared with CR group, more patients in NR group had FLT3-ITD mutation (P = 0.006) and worse physical condition (P = 0.006). More patients received unrelated donor transplantation (P = 0.027) and fewer received re-induction chemotherapy (P = 0.002). The 5-year OS was 46% in CR group and 18% in NR group. The cumulative 5-year recurrence rate was 45% and 81% in NR group, respectively. However, the 5-year NRM of the two groups was similar (28% and 30% respectively). Age, sex, FAB typing, risk stratification, and physical fitness distribution were similar in both groups. The 5-year expected OS of MRDneg patients and MDRPOS patients were 51% and 41% (P = 0.37), 55% and 36% (P = 0.20), and 29% (P = 0.43) respectively. Univariate analysis of all patients revealed that non-M5/M6 AML was inherited by low-risk group cells. Multivariate analysis showed that CR status before transplantation (risk ratio [HR] = 0.31, 95% CI 0.12-0.81, P = 0.017) and better physical fitness status score (Zubrod-ECOG-WHO 3) were associated with better prognosis. 5/M6 AML, low-risk group cytogenetics and molecular genetics, FLT3-ITD mutation negative, good physical fitness status and the number of chemotherapy courses less than 4 times were positively correlated with the survival rate of patients. Multivariate analysis found that three independent prognostic factors were associated with longer survival time (Zubrod-ECOG-WHO 3) (HR = 0.13, 95% CI 0. 045-0.391, P 0.001), cytogenetic low/intermediate risk group (HR = 0.30, 95% CI0.103-0.853, P = 0.026) and non-FLT3/ITD mutation (HR = 0.22, 95% CI 0.058-0.831, P = 0.024). 2. Preliminary study on clonal evolution of relapse cloning after treatment of AML with allo-HSCT (1) Characteristics of gene mutation in 23 patients with AML at first diagnosis The highest frequency of gene abnormalities was FLT3 mutation, followed by TET2 mutation and MLL fusion gene. Survival analysis showed that patients with FLT3 mutation and MLL fusion gene seemed to have worse prognosis. FLT3 inhibitors could increase the induced remission rate and improve the prognosis of FLT3-ITD patients (33% vs. 75% in 2 years OS) after initial diagnosis and transplantation. The most common four mutations were FLT3, DNMT3A, CEBPA and NPM1. The most common mutations involved in signal pathway and epigenetic regulation were FLT3 and TET2. MSH3 was the most frequent mutation in the first relapse after transplantation. KMT2C, TSC2, WT1 and NOTCH2. Epigenetics and tumor suppressor gene mutations were the most common. TSC2, TNFAIP3, IGF1R and WT1 were the most common in refractory recurrence patients. Notch2 gene mutations occurred only in the recurrence after transplantation, and were not found at first diagnosis. Three of the four patients were cloned in the recurrence after transplantation. Three patterns of clonal evolution during post-transplant recurrence were observed: (1) There was no difference in gene mutation between post-transplant recurrence and initial diagnosis, i.e. a group of new clones appeared during recurrence. (2) New gene abnormalities were acquired on the basis of initial diagnosis of gene abnormalities during post-transplant recurrence. (3) One or more gene abnormalities were missing during post-transplant recurrence. The expression and function of Notch2 gene in adult AML patients (1) The expression level of Notch2 gene m RNA in AML patients was higher than that in normal control group (P 0.05) and ALL group (P = 0.180). According to FAB classification, the expression of Notch2 gene m RNA in AML patients was higher than that in normal control group (P 0.05) and ALL group (P = 0.180). The relative expression of Notch2 m RNA was 0.07494 in 3 patients and 0.04637 in other groups (P = 0.174). According to the karyotype grouping, the expression of Notch2 in the group with t (15,17) karyotype and the group with 11q23/MLL were 0.07494 and 0.06200, respectively. The median expression of Notch2 m RNA in other karyotypes was 0.04762 (P = 0.22). Kaplan-Meier analysis showed that the 2-year DFS in the high-expression group of Notch2 gene m RNA (relative expression (>0.04)) was higher than that in the low-expression group (relative expression 0.04) (2-year DFS was 51% and 17%, respectively, P = 0.047). The 2-year OS in the low-expression group and the high-expression group were not significantly different, 38% and 63% (P = 0.528), respectively. There was no significant correlation between the expression of Notch2 gene m RNA and prognosis in other patients with intermediate-risk karyotypes (P 0.05). (3) Overexpression of Notch2 could decrease the growth and colony-forming ability of leukemia cell line THP-1, but silencing the expression of Notch2 gene had no significant effect on its growth and proliferation. [Conclusion]1. AML patients have a better prognosis after allo-HSCT. Cell/molecular genetics and physical fitness status have a significant impact on transplantation outcomes in patients with remission before transplantation. 2. When AML patients first diagnosed and relapsed after allogeneic hematopoietic stem cell transplantation, three patterns of gene mutation may occur. Mutations involving signaling pathways and DNA methylation regulation are common, but new gene abnormalities occurring during relapse are more common in chromatin modified genes and tumor suppressor genes. CH2 can inhibit the proliferation of leukemia cell line THP-1 to some extent, but the silencing of this gene has no significant effect on the growth of leukemia cell line.
【学位授予单位】：苏州大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R733.71
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