促红细胞生成素（EPO）能够抑制药物引起的EPO受体阳性白血病细胞凋亡，促进细胞衰老，使细胞在药物治疗后得以存活。重要的是，在经历药物治疗后，一小部分衰老的细胞能够重新进入细胞周期并恢复增殖，导致疾病再发/持续存在。通过使用单细胞分析追踪退出药物诱导衰老样状态的个体细胞，我们发现细胞从衰老样状态异步退出，并表现出不同的增殖率。逃逸的细胞仍对药物治疗具有敏感性，但表现出克隆间的变异性。我们还发现，在某些逃逸的克隆中保留了衰老相关基因的表达，基因表达呈异质性。衰老的白血病细胞的基因表达发生变化，影响代谢和衰老相关分泌表型（SASP）相关基因。本文建立了一个衰老基因签名，并证明该签名是急性髓系白血病和多种其他癌症患者总体生存较差的预后标志物。部分衰老的白血病细胞依赖溶酶体活性，氯喹，一种溶酶体活性抑制剂，促使部分衰老的白血病细胞进行衰老溶解。我们的研究表明，溶血素刺激剂（ESAs）在贫血癌症患者中的严重风险可能归因于它们通过衰老程序促进了对药物具有耐受性的癌细胞。©2023. 作者。

Erythropoietin (EPO) suppresses drug-induced apoptosis in EPO-receptor-positive leukemia cells and allows cells to persist after drug treatment by promoting cellular senescence. Importantly a small proportion of senescent cells can re-enter the cell cycle and resume proliferation after drug treatment, resulting in disease recurrence/persistence. Using a single-cell assay to track individual cells that exit a drug-induced senescence-like state, we show that cells exhibit asynchronous exit from a senescent-like state, and display different rates of proliferation. Escaped cells retain sensitivity to drug treatment, but display inter-clonal variability. We also find heterogeneity in gene expression with some of the escaped clones retaining senescence-associated gene expression. Senescent leukemia cells exhibit changes in gene expression that affect metabolism and senescence-associated secretory phenotype (SASP)-related genes. Herein, we generate a senescence gene signature and show that this signature is a prognostic marker of worse overall survival in AML and multiple other cancers. A portion of senescent leukemia cells depend on lysosome activity; chloroquine, an inhibitor of lysosome activity, promotes senolysis of some senescent leukemia cells. Our study indicates that the serious risks associated with the use of erythropoietin-stimulating agents (ESAs) in anemic cancer patients may be attributed to their ability to promote drug-tolerant cancer cells through the senescence program.© 2023. The Author(s).