Journal article
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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 14.8MB, Terms of use)
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- Publisher copy:
- 10.1038/s41588-023-01480-1
Authors
- Publisher:
- Springer Nature
- Journal:
- Nature Genetics More from this journal
- Volume:
- 55
- Issue:
- 9
- Pages:
- 1531–1541
- Place of publication:
- United States
- Publication date:
- 2023-09-04
- Acceptance date:
- 2023-07-20
- DOI:
- EISSN:
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1546-1718
- ISSN:
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1061-4036
- Pmid:
-
37666991
- Language:
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English
- Keywords:
- Pubs id:
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1522015
- Local pid:
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pubs:1522015
- Deposit date:
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2024-01-10
- ARK identifier:
Terms of use
- Copyright holder:
- Rodriguez-Meira et al.
- Copyright date:
- 2023
- Rights statement:
- © The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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