Notch1 Provides a Proliferative Signal in Mouse T Cell Leukemia by Directly Targeting c-Myc.

Abstract

As demonstrated in mouse models and in primary human T cell leukemic samples, 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 γ-secretase-dependent process that releases intracellular Notch1 from the membrane to the nucleus where it forms part of a transcriptional activator complex. We have demonstrated that mouse leukemic growth is Notch1-dependent, since treatment with γ-secretase inhibitors (GSI) results in rapid cell cycle arrest and/or apoptosis. To specifically identify Notch1 target gene(s) in leukemia, we developed mouse T cell leukemic cell lines that express intracellular Notch1 in a doxycycline-dependent manner. Using gene expression profiling and chromatin immunoprecipitation, we identified c-myc as a novel and direct Notch1 target gene. Consistent with these findings, retroviral insertional mutagenesis screening of our tal1 leukemic mouse model reveal common insertions in either notch1 or c-myc. Retroviral expression of c-myc, like intracellular Notch1, rescues the growth arrest and apoptosis associated with GSI treatment or Notch1 inhibition in 83% mouse tal1 leukemic cell lines tested. Yet in a subset of leukemic cell lines, retroviral expression of c-myc fails to rescue leukemic growth, whereas expression of intracellular Notch1 in these lines remains capable of restoring growth. These data suggest that additional Notch1 target genes other than c-myc contribute to leukemogenesis. Other Notch1 target genes in thymocyte developement and their potential role in leukemogenesis will be discussed.