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 VM, Calvo JA, Draheim KM, Cunningham LA, Hermance NM, Beverly LJ, Krishnamoorthy V, Bhasin M, Capobianco AJ, Kelliher MA. (2006). Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. GSBS Student Publications. https://doi.org/10.1128/MCB.01091-06. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1105