Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital "Carl Gustav Carus", TU Dresden, 01307 Dresden, Germany.
Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany.
Int J Mol Sci. 2021 Oct 26;22(21):11572. doi: 10.3390/ijms222111572.
While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregulation of this process is tightly linked to malignant transformation and cancer. Here, we present the novel finding of a germline stop-gain variant (p.Q199*) in the shelterin complex gene , which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated display increased DNA damage and chromosomal instabilities compared to the wildtype counterpart. Protein and mRNA expression analyses in the primary patient cells further confirm that, physiologically, the variant leads to a nonfunctional allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous p.Q199* as well as knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between p.Q199* and telomeric dysregulation and highlight germline deficiency as a predisposition to myeloid malignancies in childhood.
虽然 shelterin 复合物可保护并协调端粒调控机制，但该过程的失调与恶性转化和癌症密切相关。在这里，我们提出了一个新的发现，即在一个患有急性髓细胞白血病的儿童中，发现了 shelterin 复合物基因中的一个胚系终止增益变异（p.Q199*）。我们表明，与野生型相比，过表达突变 的细胞显示出增加的 DNA 损伤和染色体不稳定性。在原代患者细胞中的蛋白和 mRNA 表达分析进一步证实，在生理上，该变体导致患者的 等位基因无功能。随后对携带杂合子 p.Q199的原代细胞以及 knockdown AML 细胞进行端粒长度测量，发现端粒延长是主要的功能效应。这些结果表明 p.Q199与端粒失调之间存在联系，并强调了 种系缺陷是儿童骨髓恶性肿瘤的易感性。
