A heterozygousCEBPAmutation disrupting the bZIP domain causes MDS disease progression

Abstract

SUMMARYMyelodysplastic syndrome disease (MDS) has a variable risk for progression to AML. Mutations inCEBPAare 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 mutantCEBPAas causative for MDS disease progression, providing a new isogenic MDS experimental model for drug screening to improve diagnostic and therapeutic strategies.HighlightsDevelopment of isogenic iPSC model of clonal evolution of MDSMonoallelic disruption of CEBPA bZIP domain is causative for MDS disease progressionMonoallelic disruption of CEBPA bZIP reshapes chromatin landscapePatient derived iPSCs recapitulate drug responsiveness