英国牛津大学Adam J. Mead等研究人员合作发现，单细胞多组学确定慢性炎症是TP53突变白血病演化的驱动因素。2023年9月4日，《自然—遗传学》杂志在线发表了这一最新研究成果。

研究人员对骨髓增生性肿瘤患者的造血干细胞/祖细胞（HSPC）进行了等位基因解析单细胞多组学分析，这些患者转变为肿瘤蛋白53（TP53）突变的继发性急性髓性白血病（sAML）。所有患者在转化时都显示出显性TP53“多命中”HSPC克隆，其白血病干细胞转录特征可强烈预测独立队列中TP53突变型和野生型（WT）急性髓细胞性白血病的不良预后。

通过对序列样本、先证TP53杂合克隆和体内扰动的分析，研究人员证明了迄今为止尚未认识到的慢性炎症效应，它抑制了TP53 WT HSPC，同时增强了TP53突变细胞的适应优势，促进了基因演化。这些发现将促进TP53突变型白血病的风险分级、早期检测和治疗策略的发展，并对其他癌症类型具有广泛的意义。

据介绍，了解TP53突变驱动的克隆演化和后续转化的遗传和非遗传决定因素是设计合理治疗策略的关键一步。

附：英文原文

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

Author: Rodriguez-Meira, Alba, Norfo, Ruggiero, Wen, Sean, Chdeville, Agathe L., Rahman, Haseeb, OSullivan, Jennifer, Wang, Guanlin, Louka, Eleni, Kretzschmar, Warren W., Paterson, Aimee, Brierley, Charlotte, Martin, Jean-Edouard, Demeule, Caroline, Bashton, Matthew, Sousos, Nikolaos, Moralli, Daniela, Subha Meem, Lamia, Carrelha, Joana, Wu, Bishan, Hamblin, Angela, Guermouche, Helene, Pasquier, Florence, Marzac, Christophe, Girodon, Franois, Vainchenker, William, Drummond, Mark, Harrison, Claire, Chapman, J. Ross, Plo, Isabelle, Jacobsen, Sten Eirik W., Psaila, Bethan, Thongjuea, Supat, Antony-Debr, Ilana, Mead, Adam J.

Issue&Volume: 2023-09-04

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.

DOI: 10.1038/s41588-023-01480-1

Source: https://www.nature.com/articles/s41588-023-01480-1