了解肿瘤蛋白53（TP53）突变驱动的克隆演化和随后的转化的遗传和非遗传决定因素，对于设计合理的治疗策略是至关重要的一步。在这里，我们对转化为TP53突变的二次急性骨髓白血病（sAML）的骨髓增殖性肿瘤患者的造血干/祖细胞（HSPCs）进行等位分辨单细胞多组学分析。所有患者在转化时都显示出主导性的TP53 "多命中点" HSPC克隆，这些克隆在TP53突变和野生型（WT）AML的独立队列中强烈预测不良结果的白血病干细胞转录标志。通过对序列样本、前驱性TP53杂合克隆和体内干扰的分析，我们展示了慢性炎症的一个迄今未知的影响，即抑制了TP53 WT HSPCs的同时增强了TP53突变细胞的适应优势并促进了遗传演化。我们的发现将有助于发展TP53突变性白血病的风险分层、早期检测和治疗策略，并对其他癌症类型具有广泛的相关性。©2023. 作者。

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.© 2023. The Author(s).