中国儿童急性淋巴细胞性白血病染色体6q16.3~21区域候选肿瘤抑制基因的定位与鉴定
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国家自然科学基金资助项目(30571982, 30270722).


Identification of Candidate Tumor Suppressor Genes in Childhood Acute Lymphoblastic Leukemia at Chromosome 6q16.3~21 in China
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This work was supported by grants from The National Natural Science Foundation of China (30571982 and 30270722).

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    摘要:

    为了克隆儿童急性淋巴细胞性白血病 (ALL) 候选肿瘤抑制基因,首先选取分布于6q16.3~21上的11个多态性微卫星标记,对139例中国儿童ALL标本进行杂合性缺失 (LOH) 分析. 分析显示32%的患者存在至少一个位点的LOH,且高频缺失区位于D6S1709~D6S301之间,大小为2cM. 各位点LOH与白细胞总数、病态细胞数有显著性相关 (P < 0.05) ,与年龄、性别、形态学分型和免疫学分型无显著相关 (P > 0.05). 进一步在高频缺失区域内,采用定位候选克隆策略、生物信息学技术及RT-PCR技术筛选、鉴定与儿童ALL相关的候选肿瘤抑制基因及其cDNA片段. 在D6S1709~D6S301之间筛选到一个在儿童ALL细胞中低表达的EST (GenBank登录号:AA403058),与正常外周血单个核细胞比较,在15例ALL患者中有10例表达下调 (P < 0.05). 采用数字化差异表达分析显示,位于6q16.3~21区域内的AMD1基因、PPIL6基因和WASF1基因在肿瘤组织中的表达丰度要低于正常组织 (P < 0.05). 上述结果为进一步在6q16.3~21区域克隆肿瘤抑制基因提供了线索.

    Abstract:

    In order to identify candidate tumor suppressor genes (TSGs) in childhood acute lymphoblastic leukemia (ALL), firstly, loss of heterozygosity (LOH) of 6q16.3~21 in 139 primary ALL samples was analyzed by using polymerase chain reaction (PCR) and 11 microsatellite markers. The frequency of LOH on 6q16.3~21 was 32%. A 2-cM high frequency deletion region was flanked by D6S1709 and D6S301 loci at 6q16.3~21. Clinical data showed that patient with 6q16.3~21 LOH had higher WBC counts and blast cells (P < 0.05). The statistics about age, sex, classification of morphology and immunology were indistinct (P > 0.05). Then, positional cloning strategy, bioinformatics technology and reverse transcription-polymerase chain reaction (RT-PCR) were used to identify candidate TSGs and its cDNA fragments at 6q16.3~21, especially at the high frequency deletion region. Comparing with expression of normal peripheral blood mononuclear cell, EST screened in D6S1709-D6S301(GenBank Accession No.AA403058) was down-regulation in ten of fifteen childhood ALL (P < 0.05). Digital differential display showed that the expression levels of AMD1, PPIL6 and WASF1 were lower in cancer tissues than in normal tissues(P < 0.05). These findings may provide new clues in cloning of childhood ALL TSGs at 6q16.3~21.

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康 睿,曹励之,俞 燕,杨明华,张朝霞,郭碧贇,谢 岷,陈 英,谭志红,王 卓,胡 婷,吴秀山.中国儿童急性淋巴细胞性白血病染色体6q16.3~21区域候选肿瘤抑制基因的定位与鉴定[J].生物化学与生物物理进展,2006,33(1):65-71

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