Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, 835 South Wolcott Avenue, E705 MSB (MC 790), Chicago, IL 60612, USA.
Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, IL, USA.
Stem Cell Reports. 2022 Apr 12;17(4):879-893. doi: 10.1016/j.stemcr.2022.02.010. Epub 2022 Mar 17.
DDX41 is a tumor suppressor frequently mutated in human myeloid neoplasms, but whether it affects hematopoiesis is unknown. Using a knockout mouse, we demonstrate that DDX41 is required for mouse hematopoietic stem and progenitor cell (HSPC) survival and differentiation, particularly of myeloid lineage cells. Transplantation of Ddx41 knockout fetal liver and adult bone marrow (BM) cells was unable to rescue mice from lethal irradiation, and knockout stem cells were also defective in colony formation assays. RNA-seq analysis of Lin/cKit/Sca1Ddx41 knockout cells from fetal liver demonstrated that the expression of many genes associated with hematopoietic differentiation were altered. Furthermore, differential splicing of genes involved in key biological processes was observed. Our data reveal a critical role for DDX41 in HSPC differentiation and myeloid progenitor development, likely through regulating gene expression programs and splicing.
DDX41 是一种在人类髓系肿瘤中经常发生突变的肿瘤抑制因子，但它是否影响造血功能尚不清楚。利用敲除小鼠，我们证明 DDX41 对于小鼠造血干细胞和祖细胞（HSPC）的存活和分化是必需的，特别是对于髓系细胞。将 Ddx41 敲除的胎肝和成年骨髓（BM）细胞移植到小鼠体内，无法使其免受致死性照射的影响，而且敲除的干细胞在集落形成测定中也存在缺陷。对来自胎肝的 Lin/cKit/Sca1 Ddx41 敲除细胞进行 RNA-seq 分析表明，许多与造血分化相关的基因的表达发生了改变。此外，还观察到参与关键生物学过程的基因的可变剪接。我们的数据揭示了 DDX41 在 HSPC 分化和髓系祖细胞发育中的关键作用，可能是通过调节基因表达程序和剪接。
