Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival
Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival
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DOI：
10.3324/haematol.2011.054361
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发表时间：
2012-06-01
期刊：
影响因子：
--
通讯作者：
Owen, Carolyn
中科院分区：
文献类型：
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作者：
Boedoer, Csaba;Renneville, Aline;Owen, Carolyn
虽然大多数骨髓增生异常综合征/急性髓系白血病病例是散发性的，但罕见的家族性病例也会发生，并为白血病的发生提供了一些见解。最明确定义的家族性病例是由RUNX1或CEBPA的遗传突变引起的。最近，GATA2的新的种系突变被报道。因此，我们调查了患有骨髓增生异常综合征/带有野生型RUNX1和CEBPA的急性髓系白血病患者的一个或多个一级亲属的个体，以寻找GATA2突变。还进行了其他复发突变的筛查。在一家系中观察到GATA2 p Thr354Met突变，其中两个一级表亲发展为高危骨髓增生异常综合征伴7号单体。他们也被观察到获得了相同的体细胞ASXL1突变，尽管进行了干细胞移植，但两人都死亡。这些发现证实了胚系GATA2突变易患家族性骨髓增生异常综合征/急性髓系白血病，而7号单体和ASXL1突变可能是在这些家系中反复发生的继发性遗传异常，引发明显的恶性肿瘤。
While most myelodysplastic syndrome/acute myeloid leukemia cases are sporadic, rare familial cases occur and provide some insight into leukemogenesis. The most clearly defined familial cases result from inherited mutations in RUNX1 or CEBPA. Recently, novel germline mutations in GATA2 have been reported. We, therefore, investigated individuals from families with one or more first-degree relatives with myelodysplastic syndrome/acute myeloid leukemia with wild-type RUNX1 and CEBPA, for GATA2 mutations. Screening for other recurrent mutations was also performed. A GATA2 p. Thr354Met mutation was observed in a pedigree in which 2 first-degree cousins developed high-risk myelodysplastic syndrome with monosomy 7. They were also observed to have acquired identical somatic ASXL1 mutations and both died despite stem cell transplantation. These findings confirm that germline GATA2 mutations predispose to familial myelodysplastic syndrome/acute myeloid leukemia, and that monosomy 7 and ASXL1 mutations may be recurrent secondary genetic abnormalities triggering overt malignancy in these families.