학술논문
Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution
Document Type
Article
Author
Rodriguez-Meira, Alba; Norfo, Ruggiero; Wen, Sean; Chédeville, Agathe L.; Rahman, Haseeb; O’Sullivan, Jennifer; Wang, Guanlin; Louka, Eleni; Kretzschmar, Warren W.; Paterson, Aimee; Brierley, Charlotte; Martin, Jean-Edouard; Demeule, Caroline; Bashton, Matthew; Sousos, Nikolaos; Moralli, Daniela; Subha Meem, Lamia; Carrelha, Joana; Wu, Bishan; Hamblin, Angela; Guermouche, Helene; Pasquier, Florence; Marzac, Christophe; Girodon, François; Vainchenker, William; Drummond, Mark; Harrison, Claire; Chapman, J. Ross; Plo, Isabelle; Jacobsen, Sten Eirik W.; Psaila, Bethan; Thongjuea, Supat; Antony-Debré, Iléana; Mead, Adam J.
Source
Nature Genetics; September 2023, Vol. 55 Issue: 9 p1531-1541, 11p
Subject
Language
ISSN
10614036; 15461718
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 TP53WT 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.