Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution
Alba Rodríguez-Meira, Ruggiero Norfo, Sean Wen, Agathe L. Chédeville, Haseeb Rahman, Jennifer O’Sullivan, Guanlin Wang, Eleni Louka, Warren W. Kretzschmar, Aimee Paterson, Charlotte Brierley, Jean‐Edouard Martin, Caroline Demeule, Matthew Bashton, Nikolaos Sousos, Daniela Moralli, Lamia Subha Meem, Joana Carrelha, Bishan Wu, Angela Hamblin, Hélène Guermouche, Florence Pasquier, Christophe Marzac, François Girodon, William Vainchenker, Mark W. Drummond, Claire Harrison, J. Ross Chapman, Isabelle Plo, Sten Eirik W. Jacobsen, Bethan Psaila, Supat Thongjuea, Iléana Antony‐Debré, Adam J. Mead
Abstract
Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 'multihit' HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53 WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types.