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

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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.
Funding Information
  • Cancer Research UK (C42639/A26988, C5255/A20936)
  • RCUK | Medical Research Council (MC_PC_19049, MC_PC_19049)
  • Wellcome Trust (222800/Z/21/Z)
  • Emergence Canceropole Ile de France, Association pour la Recherche contre le cancer, Siric-Socrate, INCA-PLBIO

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