Schindler Jeffrey W, Van Buren Denille, Foudi Adlen, Krejci Ondrej, Qin Jinzhong, Orkin Stuart H, Hock Hanno
Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Cell Stem Cell. 2009 Jul 2;5(1):43-53. doi: 10.1016/j.stem.2009.04.019.
The initial steps in the pathogenesis of acute leukemia remain incompletely understood. The TEL-AML1 gene fusion, the hallmark translocation in Childhood Acute Lymphoblastic Leukemia and the first hit, occurs years before the clinical disease, most often in utero. We have generated mice in which TEL-AML1 expression is driven from the endogenous promoter and can be targeted to specific populations. TEL-AML1 renders mice prone to malignancy after chemical mutagenesis when expressed in hematopoietic stem cells (HSCs), but not in early lymphoid progenitors. We reveal that TEL-AML1 markedly increases the number of HSCs and predominantly maintains them in the quiescent (G(0)) stage of the cell cycle. TEL-AML1(+) HSCs retain self-renewal properties and contribute to hematopoiesis, but fail to out-compete normal HSCs. Our work shows that stem cells are susceptible to subversion by weak oncogenes that can subtly alter their molecular program to provide a latent reservoir for the accumulation of further mutations.
急性白血病发病机制的初始步骤仍未完全明确。TEL-AML1基因融合是儿童急性淋巴细胞白血病的标志性易位及首个致病因素，它在临床疾病出现前数年就已发生，多数情况下是在子宫内。我们培育出了这样的小鼠，其中TEL-AML1的表达由内源性启动子驱动，且可靶向特定细胞群体。当在造血干细胞（HSCs）中表达时，TEL-AML1使小鼠在化学诱变后易于发生恶性肿瘤，但在早期淋巴祖细胞中表达时则不然。我们发现，TEL-AML1显著增加了造血干细胞的数量，并主要将它们维持在细胞周期的静止（G(0)）阶段。TEL-AML1(+)造血干细胞保留自我更新特性并参与造血，但无法胜过正常造血干细胞。我们的研究表明，干细胞易受弱致癌基因的颠覆，这些基因可微妙地改变其分子程序，为进一步突变的积累提供潜在库。
