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NATURE GENETICS
Volume -, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-023-01480-1
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This study analyzes hematopoietic stem/progenitor cells from patients with secondary acute myeloid leukemia (sAML) transforming from myeloproliferative neoplasm. They find that chronic inflammation suppresses TP53 wild-type cells while enhancing the fitness advantage of TP53-mutant cells, promoting genetic evolution. These findings will aid in the development of risk-stratification, early detection, and treatment strategies for TP53-mutant leukemia.
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.
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