A heterozygous CEBPA mutation disrupting the bZIP domain in a RUNX1 and SRSF2 mutational background causes MDS disease progression
- Ruba Almaghrabi
- Yara Alyahyawi
- 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 García
2025-07-01
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.