Centre for Haematology, Hammersmith Campus, Imperial College London, London, United Kingdom;
Blood. 2013 Dec 5;122(24):3908-17. doi: 10.1182/blood-2013-07-515148. Epub 2013 Sep 10.
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 ∼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.
一过性髓系增生异常（TAM）是一种独特于唐氏综合征（DS）新生儿的白血病前期疾病，可能转化为儿童急性髓系白血病（ML-DS）。TAM 和 ML-DS 中均存在获得性 GATA1 突变。目前的 TAM 定义既没有规定blasts 的百分比，也没有规定 GATA1 突变分析的作用。为了定义 TAM，我们前瞻性地分析了 200 例 DS 新生儿的临床发现、血细胞计数和涂片以及 GATA1 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 例中的 195 例（97.5%）有循环blasts。通过 Sanger 测序/变性高效液相色谱（Ss/DHPLC）在 200 例中的 17 例（8.5%）中检测到 GATA1 突变，所有这些突变都伴有 >10%的blasts。此外，通过靶向下一代重测序（NGS）在 88 例中（20.4%；敏感性约为 0.3%）无 Ss/DHPLC 可检测到 GATA1 突变的 DS 新生儿中检测到低丰度 GATA1 突变克隆。这些 18 例新生儿没有任何临床或血液学特征可以区分。我们建议将术语“沉默性 TAM”用于仅通过 NGS 可检测到 GATA1 突变的 DS 新生儿。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 GATA1 突变和血细胞计数及涂片分析。Ss/DHPLC 可用于初始筛查，但如果 Ss/DHPLC 无法检测到 GATA1 突变，则可以使用基于 NGS 的方法识别带有小 GATA1 突变克隆的新生儿。
