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.

DDX41 种系杂合突变使个体在成年后易患血液系统恶性肿瘤。大多数 DDX41 突变都会导致蛋白质截短，从而导致蛋白质功能丧失。为了研究这些突变对造血功能的影响，我们培育了一种 Ddx41 等位基因造血特异性敲除的小鼠。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，并在衰老时出现造血衰竭。对移植骨髓中 HSPC 亚群的转录组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 ^+/- HSPC 的表型，我们生成了具有组合 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的适应性缺陷。然而，Ddx41 和 Trp53 突变小鼠很容易患上类似于人类骨髓增生异常综合征和急性髓系白血病的血液恶性肿瘤。总之，DDX41 杂合性导致造血应激反应失调，从而增加了 p53 突变转化的风险。