Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution Journal Article
| Authors: | Rodriguez-Meira, A.; Norfo, R.; Wen, S.; Chédeville, A. L.; Rahman, H.; O’Sullivan, J.; Wang, G.; Louka, E.; Kretzschmar, W. W.; Paterson, A.; Brierley, C.; Martin, J. E.; Demeule, C.; Bashton, M.; Sousos, N.; Moralli, D.; Subha Meem, L.; Carrelha, J.; Wu, B.; Hamblin, A.; Guermouche, H.; Pasquier, F.; Marzac, C.; Girodon, F.; Vainchenker, W.; Drummond, M.; Harrison, C.; Chapman, J. R.; Plo, I.; Jacobsen, S. E. W.; Psaila, B.; Thongjuea, S.; Antony-Debré, I.; Mead, A. J. |
| Article Title: | Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution |
| 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. © 2023, The Author(s). |
| Keywords: | leukemia; genetics; allele; neoplasm proteins; inflammation; alleles; protein p53; tumor protein; tumor suppressor protein p53; tp53 protein, human; humans; human; multiomics |
| Journal Title: | Nature Genetics |
| Volume: | 55 |
| Issue: | 9 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-05-01 |
| Start Page: | 1531 |
| End Page: | 1541 |
| Language: | English |
| DOI: | 10.1038/s41588-023-01480-1 |
| PUBMED: | 37666991 |
| PROVIDER: | scopus |
| PMCID: | PMC10484789 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
