Department of Cancer Biology
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.
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Copyright © 2006, American Society for Microbiology. Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.
DOI of Published Version
Mol Cell Biol. 2006 Nov;26(21):8022-31. Epub 2006 Sep 5. doi:10.1128/MCB.01091-06. Link to article on publisher's site
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.