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. 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.