Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Nature. 2017 Jul 6;547(7661):104-108. doi: 10.1038/nature22993. Epub 2017 Jun 28.
In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.
在急性髓系白血病中，尽管大多数患者在缓解后仍会复发，长期生存状况不佳。从历史上看，治疗失败被认为是由于产生耐药性的突变，这些突变可能是化疗药物的诱变特性造成的。然而，其他证据表明，耐药细胞预先存在。例如，配对诊断和复发急性髓系白血病样本的深度测序提供了直接证据，表明在某些情况下，复发是由诊断时存在的少数遗传亚克隆产生的，这些亚克隆在化疗后存活下来，这表明耐药细胞是在治疗前通过进化过程产生的，并被治疗选择。然而，治疗失败的机制和白血病再生能力仍然不清楚，因为序列分析本身并不能深入了解注定会引发复发的细胞类型。尽管白血病干细胞因其休眠和自我更新特性而与复发有关，并且白血病干细胞基因表达特征高度预测治疗失败，但实验研究主要是相关性的，白血病干细胞在急性髓系白血病复发中的作用尚未得到直接证明。在这里，通过对配对诊断/复发样本的纯化亚群和异种移植进行联合遗传和功能分析，我们在诊断时就已经鉴定出了耐药细胞，并确定了两种主要的复发模式。在某些情况下，复发源自具有造血干/祖细胞表型的稀有白血病干细胞，而在其他情况下，复发源自具有免疫表型定型白血病细胞的较大亚克隆，这些亚克隆保留了强烈的干性转录特征。不同复发模式的鉴定应该会导致改善急性髓系白血病的疾病管理和监测方法。此外，复发的两种细胞起源所基于的明显的复发模式应导致开发靶向干性以预防复发的新治疗方法的重要性。
