Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome
Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome
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DOI：
10.1182/blood-2008-11-190330
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发表时间：
2009-09-24
期刊：
影响因子：
20.3
通讯作者：
Taub, Jeffrey W.
中科院分区：
文献类型：
--
作者：
Cabelof, Diane C.;Patel, Hiral V.;Taub, Jeffrey W.
唐氏综合征（DS）儿童具有独特的遗传易感性，易患白血病，特别是与体细胞GATA 1突变相关的急性巨核细胞白血病（AMkL）。使用DS作为白血病发生模型对这种遗传易感性进行研究，对于全面了解儿童白血病具有广泛的适用性。基于GATA 1突变在DS AMkL中的作用，我们分析了GATA 1突变的突变谱，以开始阐明这些序列改变产生的可能机制。突变分析显示小插入/缺失、重复和碱基替换突变占优势，包括G：C>T：A、G：C>A：T和A：T>G：C。这种突变谱表明，潜在的氧化应激和叶酸代谢异常继发于21号染色体上的基因（例如，胱硫醚-β-合酶，超氧化物歧化酶）作为GATA 1突变的潜在原因。此外，在DS和非DS患者样本中评价的DNA修复能力提供了DS组织中碱基切除修复途径受损的证据，表明无法修复DNA损伤也可能在DS儿童发生白血病的独特易感性中发挥关键作用。提出了DS中白血病发生的模型，其中诱变是由胱硫醚-β-合酶过表达和改变的叶酸稳态驱动的，叶酸稳态随着修复DNA损伤的能力受损而变得固定。（血。2009;114：2753-2763）
Down syndrome (DS) children have a unique genetic susceptibility to develop leukemia, in particular, acute megakaryocytic leukemia (AMkL) associated with somatic GATA1 mutations. The study of this genetic susceptibility with the use of DS as a model of leukemogenesis has broad applicability to the understanding of leukemia in children overall. On the basis of the role of GATA1 mutations in DS AMkL, we analyzed the mutational spectrum of GATA1 mutations to begin elucidating possible mechanisms by which these sequence alterations arise. Mutational analysis revealed a predominance of small insertion/deletion, duplication, and base substitution mutations, including G:C>T: A, G:C>A: T, and A:T>G:C. This mutational spectrum points to potential oxidative stress and aberrant folate metabolism secondary to genes on chromosome 21 (eg, cystathionine-beta-synthase, superoxide dismutase) as potential causes of GATA1 mutations. Furthermore, DNA repair capacity evaluated in DS and non-DS patient samples provided evidence that the base excision repair pathway is compromised in DS tissues, suggesting that inability to repair DNA damage also may play a critical role in the unique susceptibility of DS children to develop leukemia. A model of leukemogenesis in DS is proposed in which mutagenesis is driven by cystathionine-beta-synthase overexpression and altered folate homeostasis that becomes fixed as the ability to repair DNA damage is compromised. (Blood. 2009;114:2753-2763)