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December 8, 2025Blood

The somatic hotspot mutation of DDX41 (p.R525H) elicits dominant-negative effects upon non-truncating germline variants, explaining similar disease risk as truncating variants.

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Authors

ESEmily StepanchickYKYael Kusne

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Overview

Research reveals dominant-negative mutation in DDX41 impacts non-truncating variants in patients with hematopoietic disorders.

Key Points

  • To investigate how non-truncating DDX41 variants predispose to Myelodysplastic Syndrome and Acute Myeloid Leukemia.
  • Characterized six recurrent non-truncating P/LP variants and three VUS on DDX41 function.
  • Used CRISPR to modify DDX41 alleles in MOLM13 human AML cells.
  • Utilized genetic complementation in murine lineage-negative bone marrow cells.
  • Non-truncating P/LP and VUS variants could rescue colony forming potential in Ddx41-deficient cells.
  • p.R525H failed to rescue colony formation and exhibited dominant-negative effects.
  • Homozygous mutations of some P/LP variants were not viable.

Cite This Study

Stepanchick et al. (2025) studied this question.

synapsesocial.com/papers/69362f444fa91c937236d595https://doi.org/10.1182/blood-2025-3221
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1DDX41-R525H mutation promotes dysplastic hematopoiesis via aberrant splicing of key regulators of HSC biology2025 · 1 citations
  2. 2The somatic DDX41 hot spot mutation (p.R525H) causes skewed differentiation into plasmacytoid dendritic cells in human iPSC and leukemia models2025
  3. 3DDX41 haploinsufficiency causes inefficient hematopoiesis under stress and cooperates with p53 mutations to cause hematologic malignancy2024 · 11 citations
  4. 4Granulocyte maturation and splicing defects in DDX41-mutated leukemia2025
  5. 5Leveraging paired germline and somatic analysis to improve the classification of <i>DDX41</i> variants2026 · 1 citations