Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution

• Published in: Nature genetics Vol. 55; no. 9; pp. 1531 - 1541
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.09.2023; Nature Publishing Group US
• Subjects: Acute myeloid leukemia; Alleles; Cell cycle; Cloning; Evolution; Evolution & development; Genetic transformation; Hematopoietic stem cells; Hemopoiesis; Humans; Inflammation; Inflammation - genetics; Leukemia; Leukemia - genetics; Life Sciences; Medicin och hälsovetenskap; Multiomics; Mutants; Mutation; Neoplasm Proteins; p53 Protein; Patients; Perturbation; Progenitor cells; Stem cells; Tumor Suppressor Protein p53 - genetics
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-023-01480-1

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.