Pathogenic mechanisms of ddx41 mutations in the development of myeloid malignancies

Introduction Germline DDX41 variants are implicated in late-onset myeloid neoplasms, accounting for the largest germline risk of the development of myeloid neoplasms. In typical cases, a germline loss-of-function allele is compounded by the somatic R525H mutation affecting the helicase domain in the remaining allele. The molecular mechanism by which DDX41 mutations lead to myeloid neoplasms remains to be elucidated. Methods To delineate the pathogenic mechanism of DDX41-mutated myeloid neoplasms, we generated mice models carrying the conditional Ddx41 knock-out and/or R525H knock-in alleles. Results In non-competitive bone marrow (BM) transplantation, most of the mice reconstituted with Ddx41−/− or Ddx41R525H/− BM died within a month due to severe BM failure. In competitive transplantation, Ddx41−/− and Ddx41R525H/− mice-derived cells showed markedly disadvantageous reconstitution, while Ddx41+/− and Ddx41R525H/+ mice-derived cells showed slightly reduced reconstitution compared to Ddx41+/+ mice-derived cells. By contrast, the mice transplanted with Ddx41+/− or Ddx41R525H/+ BM showed significantly reduced WBC counts and anemia in long-term observation in both primary and serial transplantations. Some of the Ddx41+/− or Ddx41R525H/+ BM-transplanted mice exhibited MDS-like phenotypes, showing ineffective hematopoiesis with evidence of erythroid dysplasia. Transcriptome analysis of Ddx41+/− and Ddx41R525H/+ derived stem cells exhibited a significant deregulation of genes involved in RNA metabolism, ribosome biogenesis and apoptosis. Conclusions Monoallelic Ddx41 loss-of function or R525H knock-in alleles led to age-dependent impaired hematopoiesis and the development of myeloid malignancies, while compound biallelic loss-of function and R525 alleles showed a severely compromised function of hematopoietic stem cells.