| First Author | Sharma VM | Year | 2006 |
| Journal | Mol Cell Biol | Volume | 26 |
| Issue | 21 | Pages | 8022-31 |
| PubMed ID | 16954387 | Mgi Jnum | J:115969 |
| Mgi Id | MGI:3692515 | Doi | 10.1128/MCB.01091-06 |
| Citation | Sharma VM, et al. (2006) Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol Cell Biol 26(21):8022-31 |
| abstractText | Recent work with mouse models and human leukemic samples has shown that gain-of-function mutation(s) in Notch1 is a common genetic event in T-cell acute lymphoblastic leukemia (T-ALL). The Notch1 receptor signals through a gamma-secretase-dependent process that releases intracellular Notch1 from the membrane to the nucleus, where it forms part of a transcriptional activator complex. To identify Notch1 target genes in leukemia, we developed mouse T-cell leukemic lines that express intracellular Notch1 in a doxycycline-dependent manner. Using gene expression profiling and chromatin immunoprecipitation, we identified c-myc as a novel, direct, and critical Notch1 target gene in T-cell leukemia. c-myc mRNA levels are increased in primary mouse T-cell tumors that harbor Notch1 mutations, and Notch1 inhibition decreases c-myc mRNA levels and inhibits leukemic cell growth. Retroviral expression of c-myc, like intracellular Notch1, rescues the growth arrest and apoptosis associated with gamma-secretase inhibitor treatment or Notch1 inhibition. Consistent with these findings, retroviral insertional mutagenesis screening of our T-cell leukemia mouse model revealed common insertions in either notch1 or c-myc genes. These studies define the Notch1 molecular signature in mouse T-ALL and importantly provide mechanistic insight as to how Notch1 contributes to human T-ALL. |
