Summary

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. All patients showed dominant TP53 ‘ multi-hit’ HSPC clones at transformation, with a leukaemia stem cell transcriptional signature strongly predictive of adverse outcome in independent cohorts, across both TP53- mutant and wild-type AML. Through analysis of serial samples and antecedent TP53 -heterozygous clones, we demonstrate a hitherto unrecognised effect of chronic inflammation, which supressed TP53 wild-type HSPC whilst enhancing the fitness advantage of TP53 mutant cells. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53 -mutant leukaemia, and are of broader relevance to other cancer types.