Deciphering TP53 mutant Cancer Evolution with Single-Cell Multi-Omics

Rodriguez-Meira A, Norfo R, Wen WX, Chédeville AL, Rahman H, O’Sullivan J, Wang G, Louka E, Kretzschmar WW, Paterson A, Brierley C, Martin J, Demeule C, Bashton M, Sousos N, Hamblin A, Guermouche H, Pasquier F, Marzac C, Girodon F, Drummond M, Harrison C, Plo I, Jacobsen SEW, Psaila B, Thongjuea S, Antony-Debré I, Mead AJ.
Preprint from
29 March 2022


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.