TitleNotch activation inhibits AML growth and survival: a potential therapeutic approach.
Publication TypeJournal Article
Year of Publication2013
AuthorsKannan, Sankaranarayanan, Sutphin Robert M., Hall Mandy G., Golfman Leonard S., Fang Wendy, Nolo Riitta M., Akers Lauren J., Hammitt Richard A., McMurray John S., Kornblau Steven M., Melnick Ari M., Figueroa Maria E., and Zweidler-McKay Patrick A.
JournalJ Exp Med
Date Published2013 Feb 11
KeywordsAdolescent, Animals, Apoptosis, Basic Helix-Loop-Helix Transcription Factors, Cell Line, Tumor, Cell Proliferation, Cell Survival, Child, DNA-Binding Proteins, Gene Expression, Homeodomain Proteins, Humans, Infant, Leukemia, Myeloid, Acute, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Mutation, Proto-Oncogene Proteins c-bcl-2, Receptors, Notch, RNA, Messenger, RNA, Neoplasm, Signal Transduction, Transcription Factor HES-1, Transcription Factors, Tumor Suppressor Protein p53

<p>Although aberrant Notch activation contributes to leukemogenesis in T cells, its role in acute myelogenous leukemia (AML) remains unclear. Here, we report that human AML samples have robust expression of Notch receptors; however, Notch receptor activation and expression of downstream Notch targets are remarkably low, suggesting that Notch is present but not constitutively activated in human AML. The functional role of these Notch receptors in AML is not known. Induced activation through any of the Notch receptors (Notch1-4), or through the Notch target Hairy/Enhancer of Split 1 (HES1), consistently leads to AML growth arrest and caspase-dependent apoptosis, which are associated with B cell lymphoma 2 (BCL2) loss and enhanced p53/p21 expression. These effects were dependent on the HES1 repressor domain and were rescued through reexpression of BCL2. Importantly, activated Notch1, Notch2, and HES1 all led to inhibited AML growth in vivo, and Notch inhibition via dnMAML enhanced proliferation in vivo, thus revealing the physiological inhibition of AML growth in vivo in response to Notch signaling. As a novel therapeutic approach, we used a Notch agonist peptide that led to significant apoptosis in AML patient samples. In conclusion, we report consistent Notch-mediated growth arrest and apoptosis in human AML, and propose the development of Notch agonists as a potential therapeutic approach in AML.</p>

Alternate JournalJ Exp Med
PubMed ID23359069
PubMed Central IDPMC3570106
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
R01 CA138816 / CA / NCI NIH HHS / United States