新研究揭示出AML白血病複發之謎

新研究揭示出AML白血病複發之謎

在一項新的研究中，來自加拿大學健康網路（University Health Network）和多倫多大學等研究機構的研究人員將急性髓細胞性白血病（Acute myeloid leukemia, AML）複發的起源追蹤到稀少的治療抵抗性的白血病幹細胞，這些白血病幹細胞在疾病確診時尚未開始化療之前就已存在於體內。針對這種侵襲性的癌症，他們也從發生疾病複發的不同患者體內鑒定出兩種不同的幹細胞樣（stem-cell like）細胞群體。在此之前，他們已證實這種侵襲性癌症是由骨髓中的造血幹細胞開始產生的。這些發現對導致這種疾病複發的幹細胞類型提供重要的見解，並且能夠有助加快尋找新的前期療法。相關研究結果於2017年6月28日在線發表在Nature期刊上，論文標題為「Tracing the origins of relapse in acute myeloid leukaemia to stem cells」。論文通信作者為大學健康網路瑪嘉烈公主癌症中心高級研究員、多倫多大學分子遺傳學系教授John Dick博士。論文第一作者為博士後研究員Liran Shlush博士和科研副助理Amanda Mitchell博士。

Dick博士說，「我們首次將幹細胞生物學與遺傳學的知識結合在一起，鑒定出幹細胞攜帶的突變，以及這些突變彼此之間如何在AML中存在關聯。」10年前，他通過將癌基因導入正常的人血細胞中，將它們移植到異種移植模型（特殊的免疫缺陷小鼠，接受人細胞移植）中和觀察白血病產生，再現了完整的人類白血病致病過程。從那以後，這一寶貴的發現就指導著白血病研究。

為了著手解決AML複發之謎，這些研究人員分析了首次去診所時的病人血液樣品和在接受治療後發生疾病複發時的病人血液樣品。

Dick博士說，「首先，我們想知道這些血液樣品之間存在的類似性和差異。我們開展詳細的遺傳學研究，並且利用全基因組測序研究了確診時的DNA的每個部分和疾病複發時的DNA的每個部分。接著，我們研究了遺傳變化在哪些細胞中發生。」

這種兩部分方法捕獲到僅在疾病複發時觀察到的一組突變，這使得這些研究人員能夠利用幾年前在Dick實驗室開發出的 工具對白血病幹細胞和正常的幹細胞進行篩選和分類，從而將注意力集中於導致疾病複發的特定幹細胞類型上。

他說，「在5年前，這些發現是不能夠取得的，但是隨著深度測序的出現，我們能夠在正確的時間使用這種技術，並且利用它研究我們幾十年來一直在研究的課題。」

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 tranional 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 tranional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.

原文見： http://www.chance-bio.com/newsshow_392.html

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