Notch is oncogenic dominant in T-cell acute lymphoblastic leukemia

Blood. 2011 Mar 10;117(10):2901-9. doi: 10.1182/blood-2010-05-286351. Epub 2011 Jan 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Genes, myc*
  • Humans
  • Mice
  • Oncogenes / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Receptors, Notch / biosynthesis
  • Receptors, Notch / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Receptors, Notch