Prenatal origin of acute lymphoblastic leukaemia in children
Prenatal origin of acute lymphoblastic leukaemia in children
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DOI：
10.1016/s0140-6736(99)09403-9
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发表时间：
1999-10-30
期刊：
影响因子：
168.9
通讯作者：
Greaves, MF
中科院分区：
文献类型：
--
作者：
Wiemels, JL;Cazzaniga, G;Greaves, MF
背景：目前对儿童白血病的自然史或相关突变事件的发生时间还缺乏深入了解。由于染色体易位导致的TEL-AML 1基因融合在儿童急性淋巴细胞白血病的常见形式中常见。我们调查是否出现这种异常prenatally.Methods，我们确定，通过逆转录酶PCR筛查血液或骨髓，TEL-AML 1融合在12名儿童，加上一对同卵双胞胎，年龄2-5岁，从意大利和英国，谁新诊断的急性淋巴细胞白血病。采用长距离反向PCR方法对TEL-AMLI融合基因进行扩增和测序。设计了可用于短程PCR的引物，以在每个孩子的新生儿血斑中筛查患者特异性、白血病克隆特异性TEL-AMLI基因组融合序列。结果我们最初在血斑中鉴定了TEL-AMLI融合序列同卵双胞胎，4岁时被诊断患有一致性急性淋巴细胞白血病，他们共享一个单一的或克隆型的TEL-AMLI序列，这表明双胞胎中的一个是产前起源的。三个孩子被排除在外，因为控制基因不能扩增。在其他9名患者中，有6名患者的血斑呈阳性。被归类为阴性的血斑是uninformations.Interpretation我们的研究结果表明，儿童急性淋巴细胞白血病是经常发起的染色体易位事件在子宫内。然而，对同卵双胞胎的研究表明，这种事件不足以治疗临床白血病，还需要产后促进事件。
Background There is little current insight into the natural history of childhood leukaemia or the timing of relevant mutational events. TEL-AML1 gene fusion due to chromosomal translocation is frequently-seen in the common form of childhood acute lymphoblastic leukaemia. We investigated whether this abnormality arises prenatally.Methods We identified, by reverse-transcriptase PCR screening of blood or bone marrow, TEL-AML1 fusion in 12 children, plus a pair of identical twins, aged 2-5 years from Italy and the UK, who had newly diagnosed acute lymphoblastic leukaemia. We amplified and sequenced the genomic TEL-AMLI fusion gene with a long-distance inverse PCR method. Primers were designed that could be used in short-range PCR to screen for patient-specific, leukaemia clone-specific TEL-AMLI genomic fusion sequences in neonatal blood spots from each child.Findings We initially identified TEL-AMLI fusion sequences in blood spots from the identical twins, diagnosed with concordant acute lymphoblastic leukaemia at age 4 years, who shared a single or clonotypic TEL-AMLI sequence that suggested prenatal origin in one twin. Three children were excluded because control genes could not be amplified. Of the other nine patients, six had positive blood spots. Blood spots that were classified as negative were uninformative.Interpretation Our findings showed that childhood acute lymphoblastic leukaemia is frequently initiated by a chromosome translocation event in utero. Studies in identical twins show however that such an event is insufficient for clinical leukaemia and that a postnatal promotional event is also required.