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上海頌通生物科技有限公司
主營產(chǎn)品： 空間智能滅菌機器人設備，生物工程，消毒設備，滅菌設備，電話4008585180等 |
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上海頌通生物科技有限公司
主營產(chǎn)品： 空間智能滅菌機器人設備，生物工程，消毒設備，滅菌設備，電話4008585180等 |
2017-7-5
在一項新的研究中，來自加拿大學健康網(wǎng)絡（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?。ˋcute myeloid leukemia, AML）復發(fā)的起源追蹤到的治療抵抗性的白血病干細胞，這些白血病干細胞在疾病確診時尚未開始化療之前就已存在于體內(nèi)。針對這種侵襲性的癌癥，他們也從發(fā)生疾病復發(fā)的不同患者體內(nèi)鑒定出兩種不同的干細胞樣（stem-cell like）細胞群體。在此之前，他們已證實這種侵襲性癌癥是由骨髓中的造血干細胞開始產(chǎn)生的。這些發(fā)現(xiàn)對導致這種疾病復發(fā)的干細胞類型提供重要的見解，并且能夠有助加快尋找新的前期療法。相關研究結果于2017年6月28日在線發(fā)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(wǎng)絡瑪嘉烈公主癌癥中心研究員、多倫多大學分子遺傳學系教授John Dick博士。論文*作者為博士后研究員Liran Shlush博士和科研副助理Amanda Mitchell博士。
Dick博士說，“我們將干細胞生物學與遺傳學的知識結合在一起，鑒定出干細胞攜帶的突變，以及這些突變彼此之間如何在AML中存在關聯(lián)。”10年前，他通過將癌基因?qū)胝５娜搜毎?，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(chǎn)生，再現(xiàn)了完整的人類白血病致病過程。從那以后，這一寶貴的發(fā)現(xiàn)就指導著白血病研究。
為了著手解決AML復發(fā)之謎，這些研究人員分析了去診所時的病人血液樣品和在接受治療后發(fā)生疾病復發(fā)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，并且利用全基因組測序研究了確診時的DNA的每個部分和疾病復發(fā)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(fā)生。”
這種兩部分方法捕獲到僅在疾病復發(fā)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(fā)出的工具對白血病干細胞和正常的干細胞進行篩選和分類，從而將注意力集中于導致疾病復發(fā)的特定干細胞類型上。
他說，“在5年前，這些發(fā)現(xiàn)是不能夠取得的，但是隨著深度測序的出現(xiàn)，我們能夠在正確的時間使用這種技術，并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 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.
