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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.

SUBMITTER: Rodriguez-Meira A

PROVIDER: S-EPMC10484789 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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

Rodriguez-Meira Alba A Norfo Ruggiero R Wen Sean S Chédeville Agathe L AL Rahman Haseeb H O'Sullivan Jennifer J Wang Guanlin G Louka Eleni E Kretzschmar Warren W WW Paterson Aimee A Brierley Charlotte C Martin Jean-Edouard JE Demeule Caroline C Bashton Matthew M Sousos Nikolaos N Moralli Daniela D Subha Meem Lamia L Carrelha Joana J Wu Bishan B Hamblin Angela A Guermouche Helene H Pasquier Florence F Marzac Christophe C Girodon François F Vainchenker William W Drummond Mark M Harrison Claire C Chapman J Ross JR Plo Isabelle I Jacobsen Sten Eirik W SEW Psaila Bethan B Thongjuea Supat S Antony-Debré Iléana I Mead Adam J AJ

Nature genetics 20230904 9

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 ...[more]

PMID: 37666991

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Project description:BackgroundQ fever fatigue syndrome (QFS) is characterised by a state of prolonged fatigue that is seen in 20% of acute Q fever infections and has major health-related consequences. The molecular mechanisms underlying QFS are largely unclear. In order to better understand its pathogenesis, we applied a multi-omics approach to study the patterns of the gut microbiome, blood metabolome, and inflammatory proteome of QFS patients, and compared these with those of chronic fatigue syndrome (CFS) patients and healthy controls (HC).MethodsThe study population consisted of 31 QFS patients, 50 CFS patients, and 72 HC. All subjects were matched for age, gender, and general geographical region (South-East part of the Netherlands). The gut microbiome composition was assessed by Metagenomic sequencing using the Illumina HiSeq platform. A total of 92 circulating inflammatory markers were measured using Proximity Extension Essay and 1607 metabolic features were assessed with a high-throughput non-targeted metabolomics approach.ResultsInflammatory markers, including 4E-BP1 (P = 9.60-16 and 1.41-7) and MMP-1 (P = 7.09-9 and 3.51-9), are significantly more expressed in both QFS and CFS patients compared to HC. Blood metabolite profiles show significant differences when comparing QFS (319 metabolites) and CFS (441 metabolites) patients to HC, and are significantly enriched in pathways like sphingolipid (P = 0.0256 and 0.0033) metabolism. When comparing QFS to CFS patients, almost no significant differences in metabolome were found. Comparison of microbiome taxonomy of QFS and CFS patients with that of HC, shows both in- and decreases in abundancies in Bacteroidetes (with emphasis on Bacteroides and Alistiples spp.), and Firmicutes and Actinobacteria (with emphasis on Ruminococcus and Bifidobacterium spp.). When we compare QFS patients to CFS patients, there is a striking resemblance and hardly any significant differences in microbiome taxonomy are found.ConclusionsWe show that QFS and CFS patients are similar across three different omics layers and 4E-BP1 and MMP-1 have the potential to distinguish QFS and CFS patients from HC.

Dataset Information

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

Publications

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

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