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 and Paloma Garcia ()
Additional contact information
Ruba Almaghrabi: University of Birmingham
Yara Alyahyawi: University of Birmingham
Peter Keane: University of Birmingham
Syed A. Mian: The Francis Crick Institute
Khadidja Habel: The Francis Crick Institute
Amelia Atkinson: University of Birmingham
Carl Ward: University of Birmingham
Rachel Bayley: University of Birmingham
Claudia Sargas: Hospital Universitario y Politécnico La Fe
Pablo Menendez: Josep Carreras Leukemia Research Institute
George J. Murphy: Boston University School of Medicine
Turki Sobahy: King Faisal Specialist Hospital and Research Center-Jeddah
Mohammed A. Baghdadi: King Faisal Specialist Hospital and Research Center-Jeddah
Arwa F. Flemban: Umm Al-Qura University
Saeed M. Kabrah: Umm Al-Qura University
Raul Torres-Ruiz: Instituto de Salud Carlos III
Eirini P. Papapetrou: Icahn School of Medicine at Mount Sinai
Ildem Akerman: University of Birmingham
Manoj Raghavan: University of Birmingham
Eva Barragan: Hospital Universitario y Politécnico La Fe
Dominique Bonnet: The Francis Crick Institute
Constanze Bonifer: University of Birmingham
Paloma Garcia: University of Birmingham

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60192-8

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