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Perspectives
The Notch1/c-Myc Pathway in T Cell Leukemia
Vishva Mitra Sharma, Kyle M. Draheim and Michelle A. Kelliher
volume 6 | issue 8
15 April 2007Pages: 927 - 930
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The transmembrane receptor Notch1 is a member of the evolutionarily conserved family of developmental regulators originally identified in Drosophila melanogaster. Notch signaling plays essential roles in regulating cell fate in thymic, intestinal, vascular and neuronal development (1-5). Recent studies detect mutations in the Notch1 receptor in roughly half of patients with T cell acute lymphoblastic leukemia (T-ALL) (6). Although expression of an activated Notch1 allele has been shown to cause leukemia in mice, the molecular mechanisms whereby Notch1 mediates cellular transformation are unknown (7). To understand how Notch1 contributes to T cell leukemogenesis, we generated mouse leukemic cell lines where the expression of activated Notch1 was doxycycline-regulated. This cell line was used for gene expression profiling to specifically identify Notch1-regulated genes in leukemia. These studies revealed that Notch1 directly induces the expression of c-myc and that inhibition of Notch1 results in cell cycle arrest and apoptosis and decreased c-myc levels (8). These studies and those performed by Aster, Pear and colleagues in human T-ALL cell lines demonstrate that the direct Notch1-mediated activation of c-myc is required to maintain leukemic growth (8-10). Interestingly, the Notch1/c-Myc oncogenic pathway does not appear limited to T-ALL, as studies by the Efstratiadis group show that expression of intracellular Notch1 leads to mammary tumorigenesis and importantly, transformation appears at least partially c-myc dependent (11). Collectively, these studies begin to delineate how Notch1 mediates cellular transformation and raises the possibility that the Notch1/c-Myc pathway may contribute to human breast cancer and potentially other solid tumors.
Authors
Vishva Mitra Sharma
University of Massachusetts Medical School, Worcester, Massachusetts
Kyle M. Draheim
University of Massachusetts Medical School, Worcester, Massachusetts
Michelle A. Kelliher
University of Massachusetts Medical School, Worcester, Massachusetts
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.