Single-Cell Multi-Omics Identifies Chronic Inflammation as a Driver of TP53 mutant Leukaemic Evolution

TP53 is the most commonly mutated gene in human cancer, typically occurring in association with complex cytogenetics and dismal outcomes. Understanding the genetic and non-genetic determinants of TP53- mutation driven clonal evolution and subsequent transformation is a crucial step towards the design of rational therapeutic strategies. Here, we carry out allelic resolution single-cell multi-omic analysis of haematopoietic stem/progenitor cells (HSPC) from patients with a myeloproliferative neoplasm who transform to TP53- mutant secondary acute myeloid leukaemia (AML), a tractable model of TP53 -mutant cancer evolution. Overall design: We performed TARGETseq (genotyping and mRNA-sequencing from the same cell) to enable integrated mutational and gene expression analysis.