Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution
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Published:2023-09
Issue:9
Volume:55
Page:1531-1541
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ISSN:1061-4036
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Container-title:Nature Genetics
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language:en
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Short-container-title:Nat Genet
Author:
Rodriguez-Meira AlbaORCID, Norfo Ruggiero, Wen Sean, Chédeville Agathe L., Rahman Haseeb, O’Sullivan Jennifer, Wang Guanlin, Louka EleniORCID, Kretzschmar Warren W., Paterson Aimee, Brierley Charlotte, Martin Jean-Edouard, Demeule Caroline, Bashton MatthewORCID, Sousos NikolaosORCID, Moralli Daniela, Subha Meem Lamia, Carrelha Joana, Wu Bishan, Hamblin Angela, Guermouche HeleneORCID, Pasquier Florence, Marzac Christophe, Girodon FrançoisORCID, Vainchenker WilliamORCID, Drummond Mark, Harrison Claire, Chapman J. RossORCID, Plo Isabelle, Jacobsen Sten Eirik W.ORCID, Psaila BethanORCID, Thongjuea Supat, Antony-Debré IléanaORCID, Mead Adam J.ORCID
Abstract
AbstractUnderstanding 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.
Funder
Cancer Research UK RCUK | Medical Research Council Wellcome Trust Emergence Canceropole Ile de France, Association pour la Recherche contre le cancer, Siric-Socrate, INCA-PLBIO
Publisher
Springer Science and Business Media LLC
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