Two novel RUNX1 mutations in a patient with congenital thrombocytopenia that evolved into a high grade myelodysplastic syndrome.
Two novel RUNX1 mutations in a patient with congenital thrombocytopenia that evolved into a high grade myelodysplastic syndrome.
复制标题
DOI：
10.1016/j.lrr.2015.03.002
复制
发表时间：
2015
影响因子：
--
通讯作者：
Cogle, Christopher R
中科院分区：
文献类型：
--
作者：
Schmit, Jessica M;Turner, Daniel J;Hromas, Robert A;Wingard, John R;Brown, Randy A;Li, Ying;Li, Marilyn M;Slayton, William B;Cogle, Christopher R
在这里，我们报告两个新的RUNX1突变在一个先天性血小板减少症患者转化为高级别骨髓增生异常综合征与骨髓单核细胞特征。第一个突变是8外显子内的一个核苷酸碱基从鸟嘌呤替换为腺嘌呤，导致Runx1蛋白的dna结合抑制域发生无义突变。这种无义突变被怀疑是一种新生的种系突变，因为父母双方都对这种突变呈阴性。发现的第二个突变是RUNX1基因外显子5的框架内6个核苷酸碱基对插入，预计这将导致插入dna结合runt同源结构域（RHD）。该突变在同种异体造血细胞移植前出现嵌合，移植后消失，认为是体细胞突变。由于基因筛查未发现其他基因突变，推测这两种RUNX1突变的联合作用可能比单独一种RUNX1突变产生更强的显性负作用，从而导致髓系恶性肿瘤。我们报告两个新的RUNX1突变患者与血小板减少症和MDS。我们演示了第二次命中RUNX1会导致转换的MDS。同种异体移植成功治疗双RUNX1突变MDS。
Here we report two new RUNX1 mutations in one patient with congenital thrombocytopenia that transformed into a high grade myelodysplastic syndrome with myelomonocytic features. The first mutation was a nucleotide base substitution from guanine to adenine within exon 8, resulting in a nonsense mutation in the DNA-binding inhibitory domain of the Runx1 protein. This nonsense mutation is suspected a de novo germline mutation since both parents are negative for the mutation. The second mutation identified was an in-frame six nucleotide base pair insertion in exon 5 of the RUNX1 gene, which is predicted to result in an insertion in the DNA-binding runt homology domain (RHD). This mutation is believed to be a somatic mutation as it was mosaic before allogeneic hematopoietic cell transplantation and disappeared after transplant. As no other genetic mutation was found using genetic screening, it is speculated that the combined effect of these two RUNX1 mutations may have exerted a stronger dominant negative effect than either RUNX1 mutation alone, thus leading to a myeloid malignancy. We report two new RUNX1 mutations in a patient with thrombocytopenia and MDS. We demonstrate that a second hit to RUNX1 results in transformed MDS. Allogeneic transplant was successfully used to treat double RUNX1 mutant MDS.