Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21
Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21
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DOI：
10.1182/blood-2002-11-3599
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发表时间：
2003-08-01
期刊：
影响因子：
20.3
通讯作者：
Izraeli, S
中科院分区：
文献类型：
--
作者：
Rainis, L;Bercovich, D;Izraeli, S
唐氏综合症 (DS) 患者经常出现两种克隆性巨核细胞增多症：一种常见的先天性、自发消退的短暂性骨髓增殖性疾病 (TMD)，以及不太常见的儿童急性巨核细胞白血病 (AMKL)。最近，在 6 名 AMKL DS 患者中描述了 GATA1 外显子 2 的获得性突变，GATA1 是一种 X 连锁基因，编码促进巨核细胞分化的转录因子。这些突变阻止了全长 GATA1 的合成，但允许合成缺乏反式激活结构域的较短 GATA1 蛋白 (GATA1s)。为了测试突变的 GATA1 是否参与克隆性巨核细胞增殖的启动或进展为 AMKL，我们对 35 名 AMKL 或 TMD 的 DS 患者和 7 名非 DS 的 AMKL 儿童进行了 GATA1 外显子 2 突变的筛查。在 18 名患有 AMKL 的 DS 患者中的 16 名、17 名患有 TMD 的 DS 患者中的 16 名以及 2 名患有 AMKL 并获得了 21 三体性的同卵双胞胎中发现了突变。分析揭示了 GATA1 中的各种类型的突变，包括缺失/插入、剪接突变以及无义和错义点突变，所有这些都阻止全长 GATA1 的生成，但保留了 GATA1 的翻译。我们还表明，GATA1 同种型生成的可能机制是外显子 2 的选择性剪接，而不是之前提出的选择性翻译起始，或者除了选择性翻译起始之外。这些发现表明，GATA1 的获得性宫内失活突变和 GATA1 的产生经常与 21 三体性共同启动巨核细胞增殖，但不足以进展为 AMKL。
Patients with Down syndrome (DS) frequently develop 2 kinds of clonal megakaryocytosis: a common, congenital, spontaneously resolving, transient myeloproliferative disorder (TMD) and, less commonly, childhood acute megakaryoblastic leukemia (AMKL). Recently, acquired mutations in exon 2 of GATA1, an X-linked gene encoding a transcription factor that promotes megakaryocytic differentiation, were described in 6 DS patients with AMKL. The mutations prevent the synthesis of the full-length GATA1, but allow the synthesis of a shorter GATA1 protein (GATA1s) that lacks the transactivation domain. To test whether mutated GATA1 is involved in the initiation of clonal megakaryoblastic proliferation or in the progression to AMKL, we screened 35 DS patients with either AMKL or TMD and 7 non-DS children with AMKL for mutations in exon 2 of GATA1. Mutations were identified in 16 of 18 DS patients with AMKL, in 16 of 17 DS patients with TMD, and in 2 identical twins with AMKL and acquired trisomy 21. Analysis revealed various types of mutations in GATA1, including deletion/insertions, splice mutations, and nonsense and missense point mutations, all of which prevent the generation of full-length GATA1, but preserve the translation of GATA1s. We also show that the likely mechanism of generation of GATA1 isoforms is alternative splicing of exon 2 rather than, or in addition to, alternative translation initiation, as was proposed before. These findings suggest that acquired intrauterine inactivating mutations in GATA1 and generation of GATA1s cooperate frequently with trisomy 21 in initiating megakaryoblastic proliferation, but are insufficient for progression to AMKL.