A heterozygousCEBPAmutation disrupting the bZIP domain causes MDS disease progression

SUMMARY Myelodysplastic syndrome disease (MDS) has a variable risk for progression to AML. Mutations in CEBPA are associated with a high risk of disease progression, but whether this mutation is causative for AML development is unclear. To answer this question, we generated patient-derived, MDS-specific iPSCs recapitulating the patient disease phenotype upon differentiation to blood, with hematopoietic progenitor cells showing erythroid and myeloid-dysplasia. Introduction of a frameshift mutation affecting the C/EBPα bZIP domain led to disease progression, with a reduction in clonogenic potential, block in granulocyte development and increased self-renewal capacity of erythroid progenitors. ATAC-seq revealed that the acquisition of this mutation reshaped the chromatin landscape at distal cis-regulatory regions, promoting changes in clonal composition as observed by single cell RNAseq. 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. Highlights Development of isogenic iPSC model of clonal evolution of MDS Monoallelic disruption of CEBPA bZIP domain is causative for MDS disease progression Monoallelic disruption of CEBPA bZIP reshapes chromatin landscape Patient derived iPSCs recapitulate drug responsiveness