A heterozygous CEBPA mutation disrupting the bZIP domain causes MDS disease progression
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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
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Development of isogenic iPSC model of clonal evolution of MDS
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Monoallelic disruption of CEBPA bZIP domain is causative for MDS disease progression
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Monoallelic disruption of CEBPA bZIP reshapes chromatin landscape
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Patient derived iPSCs recapitulate drug responsiveness
