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.
Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution / Rodriguez-Meira, A.; Norfo, R.; Wen, S.; Chedeville, 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-Debre, I.; Mead, A. J.. - In: NATURE GENETICS. - ISSN 1061-4036. - 55:9(2023), pp. 1531-1541. [10.1038/s41588-023-01480-1]
Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution
Norfo R.;
2023
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.File | Dimensione | Formato | |
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