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December 8, 2025Blood

DDX41-R525H mutation promotes dysplastic hematopoiesis via aberrant splicing of key regulators of HSC biology

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Authors

ASAxia SongNANifemi AkinwandeDSDerek L. Stirewalt

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Overview

Somatic mutation promotes splicing defects in hematopoietic stem cells, indicating new therapeutic targets for MDS/AML.

Key Points

  • Evaluating the role of the DDX41-R525H mutation in hematopoiesis and identifying its effects on splicing of key regulators.
  • Designed a series of DDX41 variants and examined their function in MOLM-13 and THP-1 cell lines.
  • Conducted differential splicing analysis to identify mis-spliced transcripts specific to DDX41-R525H.
  • Validated findings in purified CD34+ cells from patients with various DDX41 mutations.
  • Identified over 500 mis-spliced transcripts related to DDX41-R525H in isogenic cells.
  • Confirmed aberrant splicing of SEPTIN7 and its downregulation due to a premature stop codon.
  • Demonstrated that SEPTIN7 regulates cytokinesis and HSC polarity, impacting engraftment potential.

Cite This Study

Song et al. (2025) studied this question.

synapsesocial.com/papers/69362f4e4fa91c937236d8c8https://doi.org/10.1182/blood-2025-677
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