GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia
GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia
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DOI：
10.1182/blood-2013-07-515148
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发表时间：
2013-12-05
期刊：
影响因子：
20.3
通讯作者：
Vyas, Paresh
中科院分区：
文献类型：
--
作者：
Roberts, Irene;Alford, Kate;Vyas, Paresh
短暂性异常骨髓生成（TAM）是唐氏综合征（DS）新生儿特有的白血病前期疾病，可转化为儿童急性髓细胞白血病（ML-DS）。获得性GATA 1突变存在于TAM和ML-DS中。TAM的当前定义既没有规定原始细胞的百分比，也没有规定GATA 1突变分析的作用。为了定义TAM，我们前瞻性分析了200例DS新生儿的临床表现、血细胞计数和涂片以及GATA 1突变状态。所有DS新生儿均有多种血细胞计数和涂片异常。令人惊讶的是，200人中有195人（97.5%）有循环原始细胞。通过桑格测序/变性高效液相色谱法（Ss/DHPLC）在200例中的17例（8.5%）中检测到GATA 1突变，所有原始细胞均> 10%。此外，通过靶向下一代重测序（NGS）在88例无Ss/DHPLC可检测GATA 1突变的DS新生儿中的18例（20. 4%;灵敏度与0. 3%相似）中检测到低丰度GATA 1突变克隆。这18名新生儿无临床或血液学特征。我们建议对于GATA 1突变仅能通过NGS检测到的DS新生儿使用“沉默TAM”。为了识别所有有ML-DS风险的婴儿，我们建议在DS新生儿中进行GATA 1突变和血细胞计数和涂片分析。Ss/DPHLC可用于初始筛选，但当Ss/DHPLC无法检测到GATA 1突变时，基于NGS的方法可识别具有小GATA 1突变克隆的新生儿。（血。2013;122（24）：3908-3917）
Transient abnormal myelopoiesis (TAM), a preleukemic disorder unique to neonates with Down syndrome (DS), may transform to childhood acute myeloid leukemia (ML-DS). Acquired GATA1 mutations are present in both TAM and ML-DS. Current definitions of TAM specify neither the percentage of blasts nor the role of GATA1 mutation analysis. To define TAM, we prospectively analyzed clinical findings, blood counts and smears, and GATA1 mutation status in 200 DS neonates. All DS neonates had multiple blood count and smear abnormalities. Surprisingly, 195 of 200 (97.5%) had circulating blasts. GATA1 mutations were detected by Sanger sequencing/denaturing high performance liquid chromatography (Ss/DHPLC) in 17 of 200 (8.5%), all with blasts >10%. Furthermore low-abundance GATA1 mutant clones were detected by targeted next-generation resequencing (NGS) in 18 of 88 (20.4%; sensitivity similar to 0.3%) DS neonates without Ss/DHPLC-detectable GATA1 mutations. No clinical or hematologic features distinguished these 18 neonates. We suggest the term "silent TAM" for neonates with DS with GATA1 mutations detectable only by NGS. To identify all babies at risk of ML-DS, we suggest GATA1 mutation and blood count and smear analyses should be performed in DS neonates. Ss/DPHLC can be used for initial screening, but where GATA1 mutations are undetectable by Ss/DHPLC, NGS-based methods can identify neonates with small GATA1 mutant clones. (Blood. 2013;122(24):3908-3917)