Department of Biology, York University, Toronto, ON, M3J 1P3, Canada.
Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, Canada.
Cell Death Dis. 2023 Aug 5;14(8):503. doi: 10.1038/s41419-023-06015-4.
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.
促红细胞生成素 (EPO) 通过促进细胞衰老抑制 EPO 受体阳性白血病细胞中的药物诱导凋亡，并允许细胞在药物治疗后继续存在。重要的是，一小部分衰老细胞可以在药物治疗后重新进入细胞周期并恢复增殖，从而导致疾病复发/持续存在。我们使用单细胞分析来跟踪从药物诱导的衰老样状态退出的单个细胞，结果表明细胞从衰老样状态的退出是异步的，并显示出不同的增殖速度。逃逸的细胞仍然对药物治疗敏感，但表现出克隆间的可变性。我们还发现基因表达存在异质性，一些逃逸的克隆保留了与衰老相关的基因表达。衰老的白血病细胞表现出影响代谢和与衰老相关的分泌表型 (SASP) 相关基因的基因表达变化。在此，我们生成了一个衰老基因特征，并表明该特征是 AML 和其他多种癌症总生存期较差的预后标志物。一部分衰老的白血病细胞依赖于溶酶体活性；氯喹是一种溶酶体活性抑制剂，可促进一些衰老的白血病细胞发生细胞溶解。我们的研究表明，促红细胞生成素刺激剂 (ESA) 在贫血癌症患者中的使用所带来的严重风险可能归因于它们通过衰老程序促进耐药性癌细胞的能力。
