Unraveling the Role of DDX41 in Hematopoiesis and MDS
Abstract
Myelodysplastic syndromes (MDS) are a spectrum of disorders arising from hematopoietic stem and progenitor cell (HSPC) dysfunction resulting in ineffective hematopoiesis and cytopenias. MDS in adults is largely thought to be an acquired disorder, but the recent identification of an inherited form of adult-onset MDS linked to germline mutations in the DEAD-box Helicase 41 gene (DDX41) challenges this dogma. Germline mutations in DDX41 primarily occur in the N-terminal domain leading to an early stop codon, suggesting that diminished function of DDX41 contributes to MDS initiation. DDX41 is a nucleic acid-activated ATPase linked to immunity, splicing, and R-loop regulation. All three of these processes have been implicated in MDS, thus the underlying mechanism for how DDX41 mutations contribute to hematologic malfunctioning is unclear. We demonstrated that Ddx41 regulation of R-loops is critical to restrain innate immune signaling that can trigger aberrant HSPC expansion. Elevated R-loops and innate immune signaling were also observed in human cells with lower levels of DDX41, suggesting conservation. We also defined how Ddx41 levels impact erythropoiesis. We determined that ddx41 mutants develop anemia due to decreased expansion of erythroid progenitors and ineffective differentiation. Mechanistically, we discovered that elevated DNA damage triggered a cell cycle arrest that limited erythroid expansion in ddx41 mutants. RNA-sequencing analysis revealed numerous expression and splicing changes in cell cycle and DNA repair factors that could trigger genomic instability and activate the DNA damage response. These findings have implications for understanding the etiology of MDS/AML as well as the development of novel approaches to target R-loops, DNA damage, and innate immune signaling to treat MDS/AML patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2022
- Accession Number
- AD1202186
Entities
People
- Teresa V Bowman
Organizations
- Albert Einstein College of Medicine