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December 8, 2025BloodOpen Access

The somatic DDX41 hot spot mutation (p.R525H) causes skewed differentiation into plasmacytoid dendritic cells in human iPSC and leukemia models

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Authors

JKJun‐ichiro KidaESEmily StepanchickTCTimothy M. Chlon

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Overview

Findings reveal p.R525H enhances plasmacytoid dendritic cell differentiation in hematopoietic progenitor cells, suggesting roles in myeloid malignancies.

Key Points

  • This research investigates the effects of the DDX41 p.R525H mutation on hematopoietic cell differentiation and function.
  • Generated human induced pluripotent stem cells (iPSCs) with DDX41 mutations.
  • Used doxycycline-inducible systems to study effects on cell viability and differentiation.
  • Analyzed differentiation into hematopoietic stem and progenitor cells (HSPCs) through various cytokines.
  • DDX41 p.R525H mutation led to reduced proliferation and survival in iPSCs and HSPCs.
  • Cells with the p.R525H mutation preferentially differentiated into plasmacytoid dendritic cells.
  • Increased expression of CD123 and altered interferon signaling pathways were observed in DDX41 p.R525H cells.

Cite This Study

Kida et al. (2025) studied this question.

synapsesocial.com/papers/69362f4e4fa91c937236d8c0https://doi.org/10.1182/blood-2025-678
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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 hotspot mutation of DDX41 (p.R525H) elicits dominant-negative effects upon non-truncating germline variants, explaining similar disease risk as truncating variants.2025
  3. 3Granulocyte maturation and splicing defects in DDX41-mutated leukemia2025
  4. 4DDX41 haploinsufficiency causes inefficient hematopoiesis under stress and cooperates with p53 mutations to cause hematologic malignancy2024 · 11 citations
  5. 5Unsupervised clustering of DDX41 mutants informs on the somatic landscape of single germline hits2025