新研究揭示出AML白血病复发之谜
时间：2017-07-05 阅读：937
在一项新的研究中，来自加拿大学健康网络（University Health Network）和多伦多大学等研究机构的研究人员将急性髓细胞性白血病（Acute myeloid leukemia, AML）复发的起源追踪到的治疗抵抗性的白血病干细胞，这些白血病干细胞在疾病确诊时尚未开始化疗之前就已存在于体内。针对这种侵袭性的癌症，他们也从发生疾病复发的不同患者体内鉴定出两种不同的干细胞样（stem-cell like）细胞群体。在此之前，他们已证实这种侵袭性癌症是由骨髓中的造血干细胞开始产生的。这些发现对导致这种疾病复发的干细胞类型提供重要的见解，并且能够有助加快寻找新的前期疗法。相关研究结果于2017年6月28日在线发表在Nature期刊上，论文标题为“Tracing the origins of relapse in acute myeloid leukaemia to stem cells”。论文通信作者为大学健康网络玛嘉烈公主癌症中心研究员、多伦多大学分子遗传学系教授John Dick博士。论文*作者为博士后研究员Liran Shlush博士和科研副助理Amanda Mitchell博士。
Dick博士说，“我们将干细胞生物学与遗传学的知识结合在一起，鉴定出干细胞携带的突变，以及这些突变彼此之间如何在AML中存在关联。”10年前，他通过将癌基因导入正常的人血细胞中，将它们移植到异种移植模型（特殊的免疫缺陷小鼠，接受人细胞移植）中和观察白血病产生，再现了完整的人类白血病致病过程。从那以后，这一宝贵的发现就指导着白血病研究。
为了着手解决AML复发之谜，这些研究人员分析了去诊所时的病人血液样品和在接受治疗后发生疾病复发时的病人血液样品。
Dick博士说，“首先，我们想知道这些血液样品之间存在的类似性和差异。我们开展详细的遗传学研究，并且利用全基因组测序研究了确诊时的DNA的每个部分和疾病复发时的DNA的每个部分。接着，我们研究了遗传变化在哪些细胞中发生。”
这种两部分方法捕获到仅在疾病复发时观察到的一组突变，这使得这些研究人员能够利用几年前在Dick实验室开发出的工具对白血病干细胞和正常的干细胞进行筛选和分类，从而将注意力集中于导致疾病复发的特定干细胞类型上。
他说，“在5年前，这些发现是不能够取得的，但是随着深度测序的出现，我们能够在正确的时间使用这种技术，并且利用它研究我们几十年来一直在研究的课题。”
Tracing the origins of relapse in acute myeloid leukaemia to stem cells
In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission1. 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 drugs2. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells3. 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 chemotherapy3, 4, 5, suggesting that resistant cells are generated by evolutionary processes before treatment3 and are selected by therapy6, 7, 8. 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 cells9, 10 have been linked to relapse owing to their dormancy and self-renewal properties11, 12, 13, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure14, 15, experimental studies have been primarily correlative7 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.