Heterogeneity of clonal expansion and maturation-linked mutation acquisition in hematopoietic progenitors in human acute myeloid leukemia.
Heterogeneity of clonal expansion and maturation-linked mutation acquisition in hematopoietic progenitors in human acute myeloid leukemia.
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最近的技术进步使人们认识到人类急性髓系白血病 (AML) 的遗传复杂性，但人们对潜在的祖细胞仍知之甚少，因为它们的稀有性阻碍了直接研究。我们开发了一种将缺氧、芳烃受体抑制和通过人内皮细胞提供微环境支持相结合的共培养方法来分离这些细胞。对 CD34+/CD33− 细胞长期培养后衍生的最不成熟的前体细胞进行 X 染色体失活研究，揭示了高度可治愈的 AML 中的多克隆生长，表明在更成熟的祖细胞中获得了克隆扩张所需的突变。一致的是，在具有已知互补突变的核心结合因子（CBF）白血病中，CD34+/CD33−细胞长期培养后衍生的不成熟前体细胞既不携带突变，也不单独携带CBF突变，而更成熟的前体细胞通常携带这两种突变。这些结果与那些预后不良的白血病形成鲜明对比，后者在最不成熟的前体细胞中显示出克隆优势。这些数据表明人类 AML 祖细胞之间的异质性可能具有预后和治疗意义。
Recent technological advances led to an appreciation of the genetic complexity of human acute myeloid leukemia (AML) but underlying progenitor cells remain poorly understood because their rarity precludes direct study. We developed a co-culture method integrating hypoxia, aryl hydrocarbon receptor inhibition, and micro-environmental support via human endothelial cells to isolate these cells. X-chromosome inactivation studies of the least mature precursors derived following prolonged culture of CD34+/CD33− cells revealed polyclonal growth in highly curable AMLs, suggesting mutations necessary for clonal expansion were acquired in more mature progenitors. Consistently, in core-binding factor (CBF) leukemias with known complementing mutations, immature precursors derived following prolonged culture of CD34+/CD33− cells harbored neither mutation or the CBF mutation alone, whereas more mature precursors often carried both mutations. These results were in contrast to those with leukemias with poor prognosis that showed clonal dominance in the least mature precursors. These data indicate heterogeneity among progenitors in human AML that may have prognostic and therapeutic implications.
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影响因子：
23.9
作者：
Butler JM;Nolan DJ;Vertes EL;Varnum-Finney B;Kobayashi H;Hooper AT;Seandel M;Shido K;White IA;Kobayashi M;Witte L;May C;Shawber C;Kimura Y;Kitajewski J;Rosenwaks Z;Bernstein ID;Rafii S
通讯作者：
Rafii S
影响因子：
82.9
作者：
Eppert, Kolja;Takenaka, Katsuto;Dick, John E.
通讯作者：
Dick, John E.
影响因子：
45.3
作者：
Burnett, Alan K.;Hills, Robert K.;Wheatley, Keith
通讯作者：
Wheatley, Keith
影响因子：
50.3
作者：
Goardon, Nicolas;Marchi, Emanuele;Vyas, Paresh
通讯作者：
Vyas, Paresh
影响因子：
20.3
作者：
Ailles, LE;Gerhard, B;Hogge, DE
通讯作者：
Hogge, DE