Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc

Vishva Mitra Sharma, Jennifer A. Calvo, Kyle M. Draheim, Leslie A. Cunningham, Nicole Hermance, Levi Beverly, Veena Krishnamoorthy, Manoj Bhasin, Anthony J Capobianco, Michelle A. Kelliher

Research output: Contribution to journalArticle

193 Scopus citations

Abstract

Recent work with mouse models and human Ieukemic 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 chromal in 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.

Original languageEnglish
Pages (from-to)8022-8031
Number of pages10
JournalMolecular and Cellular Biology
Volume26
Issue number21
DOIs
StatePublished - Nov 1 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Sharma, V. M., Calvo, J. A., Draheim, K. M., Cunningham, L. A., Hermance, N., Beverly, L., Krishnamoorthy, V., Bhasin, M., Capobianco, A. J., & Kelliher, M. A. (2006). Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Molecular and Cellular Biology, 26(21), 8022-8031. https://doi.org/10.1128/MCB.01091-06