Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.

中文翻译：

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胚系 GATA1s 生成突变易患具有获得性 21 三体和唐氏综合症样表型的白血病。

患有唐氏综合症的人在儿童早期患髓性白血病的风险增加，这与获得 GATA1 突变有关，这些突变会产生一种称为 GATA1 的短 GATA1 亚型。种系 GATA1s 生成突变导致男性先天性贫血。我们报告了 2 个不相关的家庭，这些家庭携带种系 GATA1 生成突变，其中数名成员在儿童早期患上了急性巨核细胞白血病。所有可评估的白血病都获得了 21 三体或 21 四体。白血病特征与唐氏综合症相关的髓细胞白血病重叠，包括小于 4 岁的发病年龄、独特的免疫表型、复杂的核型、基因表达模式和药物敏感性。这些发现表明，无论 GATA1 突变或 21 三体是主要事件还是次要事件，21 三体和 GATA1s 生成突变的组合导致了独特的骨髓性白血病，并表明 GATA1 和 21 三体之间存在独特的功能合作白血病发生。家族史还表明，胚系 GATA1s 生成突变应包括在与骨髓增生异常综合征和白血病的家族易感性相关的突变中。