DDX41-associated susceptibility to myeloid neoplasms.
DDX41-associated susceptibility to myeloid neoplasms.
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DOI：
10.1182/blood.2022017715
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发表时间：
2023-03-30
期刊：
影响因子：
20.3
通讯作者：
Godley, Lucy A.
中科院分区：
文献类型：
--
作者：
Makishima, Hideki;V. Bowman, Teresa;Godley, Lucy A.
有害的生殖系DDX41变异会增加患髓系肿瘤(MNS)的风险，较少发生淋巴系恶性肿瘤，常染色体显性遗传，估计在MN中的患病率为3%。生殖系DDX41变异体包括约占所有等位基因三分之二的截断等位基因、优先位于死盒结构域内的错义变异体和缺失变异体。在基于肿瘤的分子图谱上识别截断等位基因应该会促进生殖系遗传学测试，因为这些等位基因中有95%是生殖系。野生型DDX41等位基因的体细胞突变发生在约一半具有生殖系DDX41等位基因的MNS中，通常发生在编码解旋酶结构域的外显子上，最常见的是R525H。有害生殖系DDX41等位基因的几个方面值得注意：(1)某些变异在特定人群中很常见，(2)MN在典型的从头疾病的高龄发展，挑战遗传癌症风险总是导致年轻人疾病的范式，(3)尽管这些变异在男性和女性中频率相同，男性进展为MN的频率更高，这表明对髓系白血病的发生具有性别特异性的影响，以及(4)具有有害生殖系DDX41变异的个人在与野生型捐赠者进行异基因造血细胞移植后比其他人更多地发展为急性严重移植物抗宿主病，除非他们在移植后接受环磷酰胺，暗示了一种刺激捐赠者来源的T细胞的促炎环境。生化研究和动物模型已经证实，DDX41‘S能够与双链脱氧核糖核酸和核糖核酸相互作用：参与信使RNA剪接、核糖体RNA或小核仁RNA加工以及调节天然免疫的DNA杂交体，其破坏可能会促进炎症和肿瘤的发生。血液病下一代测序的常规使用极大地扩大了白血病患者中遗传性易感综合征的表现。由副主编Mario Cazzola介绍，这一综述系列突出了4种这样的遗传易感综合征，并为包括骨髓发育不良和髓系白血病患者的胚系基因测试的必要性提供了强有力的支持。
Deleterious germ line DDX41 variants confer risk for myeloid neoplasms (MNs) and less frequently for lymphoid malignancies, with autosomal dominant inheritance and an estimated prevalence of 3% among MNs. Germ line DDX41 variants include truncating alleles that comprise about two-thirds of all alleles, missense variants located preferentially within the DEAD-box domain, and deletion variants. The identification of a truncating allele on tumor-based molecular profiling should prompt germ line genetic testing because >95% of such alleles are germ line. Somatic mutation of the wild-type DDX41 allele occurs in about half of MNs with germ line DDX41 alleles, typically in exons encoding the helicase domain and most frequently as R525H. Several aspects of deleterious germ line DDX41 alleles are noteworthy: (1) certain variants are common in particular populations, (2) MNs develop at older ages typical of de novo disease, challenging the paradigm that inherited cancer risk always causes disease in young people, (3) despite equal frequencies of these variants in men and women, men progress to MNs more frequently, suggesting a gender-specific effect on myeloid leukemogenesis, and (4) individuals with deleterious germ line DDX41 variants develop acute severe graft-versus-host disease after allogeneic hematopoietic cell transplantation with wild-type donors more than others unless they receive posttransplant cyclophosphamide, suggesting a proinflammatory milieu that stimulates donor-derived T cells. Biochemical studies and animal models have identified DDX41’s ability to interact with double-stranded DNA and RNA:DNA hybrids with roles in messenger RNA splicing, ribosomal RNAs or small nucleolar RNAs processing, and modulation of innate immunity, disruption of which could promote inflammation and drive tumorigenesis. Routine use of next-generation sequencing of hematologic malignancies has greatly expanded the representation of hereditary predisposition syndromes among patients with leukemia. Introduced by Associate Editor Mario Cazzola, this Review Series highlights 4 such genetic predisposition syndromes and provides strong support for the need to include germ line genetic testing for patients with myelodysplasia and myeloid leukemia.
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