Göthert Joachim R, Brake Rachael L, Smeets Monique, Dührsen Ulrich, Begley C Glenn, Izon David J
Department of Hematology, University Hospital, Essen,
Blood. 2007 Nov 15;110(10):3753-62. doi: 10.1182/blood-2006-12-063644. Epub 2007 Aug 13.
The acquired activation of stem cell leukemia (SCL) during T lymphopoiesis is a common event in T-cell acute lymphoblastic leukemia (T-ALL). Here, we generated tamoxifen (TAM)-inducible transgenic mice (lck-ER(T2)-SCL) to study the consequences of acquired SCL activation during T-cell development. Aberrant activation of SCL in thymocytes resulted in the accumulation of immature CD4(+)CD8(+) (double-positive, DP) cells by preventing normal surface expression of the T-cell receptor alphabeta (TCRalphabeta) complex. SCL-induced immature DP cells were further characterized by up-regulated NOTCH1 and generated noncycling polyclonal CD8(+)TCRbeta(low) cells. The prevalence of these cells was SCL dependent because TAM withdrawal resulted in their disappearance. Furthermore, we observed that SCL activation led to a dramatic up-regulation of NOTCH1 target genes (Hes-1, Deltex1, and CD25) in thymocytes. Strikingly, NOTCH1 target gene up-regulation was already observed after short-term SCL induction, implying that enhanced NOTCH signaling is mediated by SCL and is not dependent on secondary genetic events. These data represent the basis for a novel pathway of SCL-induced leukemogenesis and provide a functional link between SCL and NOTCH1 during this process.
在T淋巴细胞生成过程中获得性干细胞白血病（SCL）的激活是T细胞急性淋巴细胞白血病（T-ALL）中的常见事件。在此，我们构建了他莫昔芬（TAM）诱导的转基因小鼠（lck-ER(T2)-SCL），以研究T细胞发育过程中获得性SCL激活的后果。胸腺细胞中SCL的异常激活通过阻止T细胞受体αβ（TCRαβ）复合物的正常表面表达，导致未成熟的CD4(+)CD8(+)（双阳性，DP）细胞积累。SCL诱导的未成熟DP细胞的进一步特征是NOTCH1上调，并产生非循环多克隆CD8(+)TCRβ(low)细胞。这些细胞的出现率依赖于SCL，因为停用TAM会导致它们消失。此外，我们观察到SCL激活导致胸腺细胞中NOTCH1靶基因（Hes-1、Deltex1和CD25）显著上调。引人注目的是，在短期SCL诱导后就已观察到NOTCH1靶基因上调，这意味着增强的NOTCH信号传导由SCL介导，且不依赖于继发性遗传事件。这些数据代表了SCL诱导白血病发生新途径的基础，并在此过程中提供了SCL与NOTCH1之间的功能联系。
