Department of Cancer Biology
Medical Subject Headings
Amyloid Precursor Protein Secretases; Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Cell Cycle; Cell Line, Tumor; Enzyme Inhibitors; Gene Expression Profiling; *Gene Expression Regulation, Neoplastic; Humans; Leukemia, T-Cell; Mice; Mutagenesis, Insertional; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-myc; Receptor, Notch1; Retroviridae
Cancer Biology | Life Sciences | Medicine and Health Sciences
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.
Molecular and cellular biology
Sharma, Vishva Mitra; Calvo, Jennifer Ann; Draheim, Kyle M.; Cunningham, Leslie A.; Hermance, Nicole M.; Beverly, Levi J.; Krishnamoorthy, Veena; Bhasin, Manoj; Capobianco, Anthony J.; and Kelliher, Michelle A., "Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc" (2006). GSBS Student Publications. 1105.