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Abstract：
Germline heterozygous mutations in DDX41 predispose individuals to hematologic malignancies in adulthood. Most of these DDX41 mutations result in a truncated protein, leading to loss of protein function. To investigate the impact of these mutations on hematopoiesis, we generated mice with hematopoietic-specific knockout of one Ddx41 allele. Under normal steady-state conditions, there was minimal effect on lifelong hematopoiesis, resulting in a mild yet persistent reduction in red blood cell counts. However, stress induced by transplantation of the Ddx41+/- BM resulted in hematopoietic stem/progenitor cell (HSPC) defects and onset of hematopoietic failure upon aging. Transcriptomic analysis of HSPC subsets from the transplanted BM revealed activation of cellular stress responses, including upregulation of p53 target genes in erythroid progenitors. To understand how the loss of p53 affects the phenotype of Ddx41+/- HSPCs, we generated mice with combined Ddx41 and Trp53 heterozygous deletions. The reduction in p53 expression rescued the fitness defects in HSPC caused by Ddx41 heterozygosity. However, the combined Ddx41 and Trp53 mutant mice were prone to developing hematologic malignancies that resemble human myelodysplastic syndrome and acute myeloid leukemia. In conclusion, DDX41 heterozygosity causes dysregulation of the response to hematopoietic stress, which increases the risk of transformation with a p53 mutation.
摘要：
DDX41中的种系杂合突变个体在成年期易患血液系统恶性肿瘤。大多数这些DDX41突变导致截短的蛋白质，导致蛋白质功能的丧失。为了研究这些突变对造血的影响，我们产生了一个Ddx41等位基因的造血特异性敲除小鼠。在正常稳态条件下，对终生造血的影响很小，导致红细胞计数轻度但持续减少。然而,Ddx41+/-BM移植引起的应激导致造血干/祖细胞（HSPC）缺陷和衰老后造血衰竭的发作。来自移植BM的HSPC亚群的转录组学分析揭示了细胞应激反应的激活，包括红系祖细胞中p53靶基因的上调。为了了解p53的缺失如何影响Ddx41+/-HSPCs的表型，我们产生了Ddx41和Trp53杂合缺失的小鼠。p53表达的减少挽救了由Ddx41杂合性引起的HSPC中的适应性缺陷。然而,Ddx41和Trp53联合突变小鼠容易发生类似于人类骨髓增生异常综合征和急性髓细胞性白血病的血液系统恶性肿瘤.总之,DDX41杂合性导致对造血应激的反应失调，这增加了p53突变转化的风险。
