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December 8, 2025Blood

SRSF2 mutation-induced CHD8 exon skipping represents a novel pathogenic mediator and therapeutic dependence in chronic myelomonocytic leukemia (CMML)

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Authors

YWYu‐Hung WangKGKristian GurashiRPRoberto Paredes

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Overview

RNA-seq reveals splicing alterations and drug resistance pathways in chronic myelomonocytic leukemia with SRSF2 mutations, implicating CHD8 as a key therapeutic target.

Key Points

  • To identify the role of SRSF2 mutations and CHD8 exon skipping in chronic myelomonocytic leukemia (CMML).
  • Conducted RNA-seq on CD34+ HSPCs and CRISPR-edited K562 cell line.
  • Performed whole-genome CRISPRKO synthetic lethality screen in isogenic K562s.
  • Utilized clonogenic assays and transcriptomic profiling to analyze CHD8 exon skipping effects.
  • Identified correspondence of SRSF2 mutations with missplicing and chromatin remodelling in CMML.
  • Revealed that CHD8 exon skipping is linked to increased proliferation and clonogenic capacity.
  • Discovered 67 genes essential for SRSF2MT cells, highlighting potential therapeutic targets.

Cite This Study

Wang et al. (2025) studied this question.

synapsesocial.com/papers/69362f4e4fa91c937236d8cbhttps://doi.org/10.1182/blood-2025-676
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Also Consider

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

  1. 1Abstract 1497: Long-read RNA-Seq reveals a novel isoform landscape of <i>SRSF2</i> -mutant chronic myelomonocytic leukemia2026
  2. 2SRSF2 mutations contribute to bone marrow immune microenvironment alterations2026
  3. 3SF3B1 mutations K700E, K666N, and R625H: Gene expression and aberrant splicing consequences2025
  4. 4MDS-associated SF3B1 mutations promote aberrant fate choice of hematopoietic stem cell via mis-splicing of mediator kinase module component CDK82025
  5. 5SRSF2 mutation induces BH3 mimetics sensitivity via BCL2L2 mis-splicing2025