Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype
Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype
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DOI：
10.1182/blood.2021011463
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发表时间：
2022-05-26
期刊：
影响因子：
20.3
通讯作者：
Cantor, Alan B.
中科院分区：
文献类型：
--
作者：
Hasle, Henrik;Kline, Ronald M.;Cantor, Alan B.
患有唐氏综合征的个体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，该突变产生称为GATA1s的短GATA1同种型。生殖系GATA1突变导致男性先天性贫血。我们报告了2个不相关的家庭，港口生殖系GATA1基因产生突变，其中几个成员在儿童早期发展为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。白血病的特征与唐氏综合征相关的髓性白血病重叠，包括发病年龄小于4岁，独特的免疫表型，复杂的核型，基因表达模式和药物敏感性。这些研究结果表明，三体21和GATA1的组合产生突变的结果在一个独特的髓系白血病的GATA1突变或三体21是原发性或继发性事件无关，并建议有一个独特的功能合作之间的GATA1和三体21白血病的发生。家族史还表明，生殖系GATA1基因突变应包括在那些与骨髓增生异常综合征和白血病的家族易感性。
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.