Notch1 Contributes to Mouse T-Cell Leukemia by Directly Inducing the Expression of c-myc

Abstract

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 γ-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 γ-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.

NOTCH1-induced T-cell leukemia in transgenic zebrafish

“…Recent studies showed that c-Myc is another direct downstream target of Notch1 and is required for pro-growth effects of activated Notch1. 32,33 Retroviral expression of c-Myc rescues the growth arrest associated with Notch1 inhibition. However, c-Myc fails to rescue all Notch-dependent cell lines from Notch withdrawal, indicating the existence of other Notch1 target genes.…”

It's T-ALL about Notch

“…Many factors that regulate cell-cycle progression are mutated in cancer resulting in deregulated cellular growth. It has been demonstrated that Notch is involved in driving cell-cycle progression by regulating genes involved in the G 1 to S-phase transition (Ronchini and Capobianco, 2000;Satoh et al, 2004;Murata et al, 2005;Sharma et al, 2006;Weng et al, 2006). Notch directly regulates D-type cyclins, which, in conjunction with cyclin-dependent kinase (cdk) 4 and cdk6 facilitate progression through the G 1 phase (Ronchini and Capobianco, 2000).…”

“…Notch induces cell-cycle progression also through direct transactivation of c-myc (Satoh et al, 2004;Sharma et al, 2006;Weng et al, 2006). Normally, c-myc is only expressed in dividing cells and induces cell-cycle progression through induction of D-type cyclins, cyclin E, cdk4 and cdc25A, as well as repression of p27 expression (reviewed in Amati et al, 1998).…”

Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation

“…10b). Given recent reports that the activated Notch1 signalling directly induces c-myc overexpression [20][21][22] and modulates Pten expression 23 , the T(14,15)-mediated c-myc overexpression and Pten deletion together may substitute functionally for Notch1 mutations, leading to T-ALL development in our model.…”