背景:作为造血致癌物,苯通过其活性代谢物如苯醌诱导人类白血病,这可能会通过增加活性氧(ROS)引起癌症相关核基因的氧化损伤。线粒体是ROS的主要调控细胞器,线粒体的遗传异常可阻碍其对ROS的调控,导致更严重的氧化损伤。突变与一些线粒体基因中的某些类型的癌症有关,但从未对白血病进行全基因组分析。
方法:患者是一名52岁女性,长期接触苯数年。她的症状主要包括反复头晕,疲劳,他们已经持续了近8年,并在诊断前的最近几周加剧。
方法:在患者住院的第二天使用含EDTA抗凝剂的真空管从患者体内抽取外周血。同时检测血常规和白血病表型的BCR/ABL基因。分离血小板用于线粒体DNA(mtDNA)提取。ATP合酶Fo亚基8(复合物V)的遗传分析,ATP合酶Fo亚基6(复合物V),细胞色素C氧化酶亚基1(复合物IV),细胞色素c氧化酶亚基2(复合物IV),细胞色素c氧化酶亚基3,Cytb,NADH脱氢酶亚基1(复合物I)(ND)1,ND2,ND3,ND4,ND5,ND6,12S-RNA,16S-RNA,tRNA-半胱氨酸,A,N,tRNA-亮氨酸,E,在血小板mtDNA中进行置换环。使用常规Sanger测序方法验证所有检测到的基因突变。
方法:患者接受伊马替尼,一种小分子激酶抑制剂,和对症治疗。
结果:治疗3个月后,血常规指标恢复正常。
结论:共发现98个突变,25个突变是移码。所有突变点中ND6基因突变率最高。首次在苯诱导的白血病中发现了帧移位。发现了血小板线粒体基因组中的许多突变,并认为该突变在苯诱导的白血病女性患者中具有潜在的致病性。苯源性白血病患者血小板线粒体基因组突变率较高,完整的基因组分析有助于充分理解疾病特征。
BACKGROUND: As a hematopoietic carcinogen, benzene induces human leukemia through its active metabolites such as benzoquinone, which may cause oxidative damage to cancer-related nuclear genes by increasing reactive oxygen species (ROS). Mitochondrion is the main regulatory organelle of ROS, genetic abnormality of mitochondrion can impede its regulation of ROS, leading to more severe oxidative damage. Mutations have been related to certain types of cancer in several mitochondrial genes, but they have never been completely analyzed genome-wide in leukemia.
METHODS: The patient was a 52-year-old female who had chronic exposure to benzene for several years. Her symptoms mainly included recurrent dizziness, fatigue, and they had lasted for nearly 8 years and exacerbated in recent weeks before diagnosis.
METHODS: Samples of peripheral blood were taken from the patient using evacuated tubes with EDTA anticoagulant on the second day of her hospitalization. At the same time blood routine and BCR/ABL genes of leukemic phenotype were tested. Platelets were isolated for mitochondrial DNA (mtDNA) extraction. The genetic analysis of ATP synthase Fo subunit 8 (complex V), ATP synthase Fo subunit 6 (complex V), cytochrome c oxidase subunit 1 (complex IV), cytochrome c oxidase subunit 2 (complex IV), cytochrome c oxidase subunit 3, Cytb, NADH dehydrogenase subunit 1 (complex I) (ND) 1, ND2, ND3, ND4, ND5, ND6, 12S-RNA, 16S-RNA, tRNA-Cysteine, A, N, tRNA-Leucine, E, displacement loop in platelet mtDNA were performed. All the detected gene mutations were validated using the conventional Sanger sequencing method.
METHODS: The patient received imatinib, a small molecule kinase inhibitor, and symptomatic treatments.
RESULTS: After 3 months treatment her blood routine test indicators were restored to normal.
CONCLUSIONS: A total of 98 mutations were found, and 25 mutations were frame shift. The ND6 gene mutation rate was the highest among all mutation points. Frame shifts were identified in benzene-induced leukemia for the first time. Many mutations in the platelet mitochondrial genome were identified and considered to be potentially pathogenic in the female patient with benzene-induced leukemia. The mutation rate of platelet mitochondrial genome in the benzene-induced leukemia patient is relatively high, and the complete genome analysis is helpful to fully comprehend the disease characteristics.