Understanding cancer pathogenesis requires knowledge of not only the specific contributory genetic mutations, but also the cellular framework in which they arise and function. Here we explore the clonal evolution of a form of childhood precursor-B cell acute lymphoblastic leukemia that is characterized by a chromosomal translocation generating a TEL-AML1 fusion gene. We identify a cell compartment in leukemic children that can propagate leukemia when transplanted in mice. By studying a monochorionic twin pair,one preleukemic and one with frank leukermia, we establish the lineal relationship between these "cancer-propagating" cells and the preleukemic cell in which the TEL-AML1 fusion first arises or has functional impact. Analysis of TEL-AML1 transduced cord blood cells suggests that TEL-AML1 functions as a first-hit mutation by endowing this preleukemic cell with altered self-renewal and survival properties.
[Science,2008;(10).1126]
參考譯文
理解癌癥的發(fā)病機(jī)制不僅需要認(rèn)識基因突變的特殊作用，還要了解細(xì)胞骨架和它們的功能。這里我們探討了一種兒童前B細(xì)胞急性淋巴細(xì)胞性白血病的克隆演變。這種病的特征之一是發(fā)生了染色體易位，產(chǎn)生了 TEL-AML1 融合基因。我們在白血病兒童的細(xì)胞中找到一個細(xì)胞區(qū)域，把這種細(xì)胞移植到老鼠身上可以產(chǎn)生白血病。通過研究一對單絨毛膜雙胞胎，一個是前白血病狀態(tài)，一個是真正的白血病患者，我們確定了“癌癥擴(kuò)散”細(xì)胞和前白血病細(xì)胞存在線性相關(guān)。TEL-AML1 的融合首先出現(xiàn)在前白血病細(xì)胞或者會對其產(chǎn)生功能影響。TEL-AML1 轉(zhuǎn)導(dǎo)的臍帶血細(xì)胞分析表明TEL-AML1 的功能可以改變前白血病細(xì)胞的自我更新和生存特性，從而可以作為突變的第一擊。
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