Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery and University of Miami Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Blood. 2011 Mar 10;117(10):2901-9. doi: 10.1182/blood-2010-05-286351. Epub 2011 Jan 7.
T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic neoplasm characterized by malignant expansion of immature T cells. Activated NOTCH (Notch(IC)) and c-MYC expression are increased in a large percentage of human T-ALL tumors. Furthermore, c-MYC has been shown to be a NOTCH target gene. Although activating mutations of Notch have been found in human T-ALL tumors, there is little evidence that the c-MYC locus is altered in this neoplasm. It was previously demonstrated that Notch and c-Myc-regulated genes have a broadly overlapping profile, including genes involved in cell cycle progression and metabolism. Given that Notch and c-Myc appear to function similarly in T-ALL, we sought to determine whether these two oncogenes could substitute for each other in T-ALL tumors. Here we report that NOTCH(IC) is able to maintain T-ALL tumors formed in the presence of exogenous NOTCH(IC) and c-MYC when exogenous c-MYC expression is extinguished. In contrast, c-MYC is incapable of maintaining these tumors in the absence of NOTCH(IC). We propose that failure of c-MYC to maintain these tumors is the result of p53-mediated apoptosis. These results demonstrate that T-ALL maintenance is dependent on NOTCH(IC), but not c-MYC, demonstrating that NOTCH is oncogenic dominant in T-ALL tumors.
T 细胞急性淋巴细胞白血病 (T-ALL) 是一种血液系统恶性肿瘤，其特征是不成熟 T 细胞的恶性扩增。在很大比例的人类 T-ALL 肿瘤中，激活的 NOTCH（ Notch(IC)）和 c-MYC 表达增加。此外，已经表明 c-MYC 是 NOTCH 的靶基因。尽管在人类 T-ALL 肿瘤中发现了 Notch 的激活突变，但很少有证据表明该 c-MYC 基因座在这种肿瘤中发生改变。先前的研究表明， Notch 和 c-MYC 调节的基因具有广泛重叠的特征，包括参与细胞周期进展和代谢的基因。鉴于 Notch 和 c-MYC 在 T-ALL 中似乎具有相似的功能，我们试图确定这两个癌基因是否可以在 T-ALL 肿瘤中相互替代。在这里，我们报告 NOTCH(IC) 能够维持在存在外源性 NOTCH(IC)和 c-MYC 的情况下形成的 T-ALL 肿瘤，而当外源性 c-MYC 表达被熄灭时。相比之下，c-MYC 不能在没有 NOTCH(IC)的情况下维持这些肿瘤。我们提出，c-MYC 不能维持这些肿瘤是由于 p53 介导的细胞凋亡所致。这些结果表明，T-ALL 的维持依赖于 NOTCH(IC)，而不是 c-MYC，表明 NOTCH 在 T-ALL 肿瘤中是致癌优势的。
