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<p>Myelodysplastic syndrome disease (MDS) is caused by the successive acquisition of mutations and thus displays a variable risk for progression to AML. Mutations in <i>CEBPA</i> are commonly associated with a high risk of disease progression, but whether they are causative for AML development is unclear. To analyse the molecular basis of disease progression we generated MDS patient-derived induced pluripotent stem cells from a low risk male patient harbouring <i>RUNX1</i>/<i>SRSF2</i> mutations. This experimental model faithfully recapitulates the patient disease phenotypes upon hematopoietic differentiation. Introduction of a frameshift mutation affecting the C/EBPα bZIP domain in cells from low-risk stages mimicks disease progression by reducing clonogenicity of myeloid cells, blocking granulopoiesis and increasing erythroid progenitor self-renewal capacity. The acquisition of this mutation reshapes the chromatin landscape at distal cis-regulatory regions and promotes changes in cellular composition as observed by single cell RNAseq. Mutant C/EBPα is therefore causative for MDS disease progression. Our work identifies mutant <i>CEBPA</i> as causative for MDS disease progression, providing a new isogenic MDS experimental model for drug screening to improve diagnostic and therapeutic strategies.</p>

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A heterozygous CEBPA mutation disrupting the bZIP domain in a RUNX1 and SRSF2 mutational background causes MDS disease progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Ruba Almaghrabi,
  • Alyahyawi Yara,
  • Peter Keane,
  • Syed A. Mian,
  • Khadidja Habel,
  • Amelia Atkinson,
  • Carl Ward,
  • Rachel Bayley,
  • Claudia Sargas,
  • Pablo Menendez,
  • George J. Murphy,
  • Turki Sobahy,
  • Mohammed A. Baghdadi,
  • Arwa F. Flemban,
  • Saeed M. Kabrah,
  • Raul Torres-Ruiz,
  • Eirini P. Papapetrou,
  • Ildem Akerman,
  • Manoj Raghavan,
  • Eva Barragan,
  • Dominique Bonnet,
  • Constanze Bonifer,
  • Paloma Garcia

摘要

Myelodysplastic syndrome disease (MDS) is caused by the successive acquisition of mutations and thus displays a variable risk for progression to AML. Mutations in CEBPA are commonly associated with a high risk of disease progression, but whether they are causative for AML development is unclear. To analyse the molecular basis of disease progression we generated MDS patient-derived induced pluripotent stem cells from a low risk male patient harbouring RUNX1/SRSF2 mutations. This experimental model faithfully recapitulates the patient disease phenotypes upon hematopoietic differentiation. Introduction of a frameshift mutation affecting the C/EBPα bZIP domain in cells from low-risk stages mimicks disease progression by reducing clonogenicity of myeloid cells, blocking granulopoiesis and increasing erythroid progenitor self-renewal capacity. The acquisition of this mutation reshapes the chromatin landscape at distal cis-regulatory regions and promotes changes in cellular composition as observed by single cell RNAseq. Mutant C/EBPα is therefore causative for MDS disease progression. Our work identifies mutant CEBPA as causative for MDS disease progression, providing a new isogenic MDS experimental model for drug screening to improve diagnostic and therapeutic strategies.