REPROGRAMMING IDENTIFIES FUNCTIONALLY DISTINCT STAGES OF CLONAL EVOLUTION IN MYELODYSPLASTIC SYNDROMES. REPROGRAMMING IDENTIFIES FUNCTIONALLY DISTINCT STAGES OF CLONAL EVOLUTION IN MYELODYSPLASTIC SYNDROMES

As part of this study, we isolated induced pluripotent stem cells (iPSCs) from a patient with TP53-mutant MDS and identified loss of chromosome 5q as a cooperating genetic event. Using RNA sequencing we found that loss of chromosome 5q dysregulates genes that maintain chromosome stability, predisposing TP53-mutant cells to chromosomal rearrangements and progression to complex karyotype. Overall design: Hematopoietic progenitors were derived from induced pluripotent stem cells heterozygous for the TP53 R209fs mutation (TP53+/-) with or without the deletion on chromosome 5q (TP53+/-;del5q). Gene expression was compared between TP53+/- and TP53+/-;del5q HPCs by RNAseq to identify genes significantly downregulated as a result of 5q loss.