Notch activation inhibits AML growth and survival: A potential therapeutic approach

Sankaranarayanan Kannan, Robert M. Sutphin, Mandy G. Hall, Leonard S. Golfman, Wendy Fang, Riitta M. Nolo, Lauren J. Akers, Richard A. Hammitt, John S. McMurray, Steven M. Kornblau, Ari M. Melnick, Maria E. Figueroa, Patrick A. Zweidler-McKay

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)321-337
Number of pages17
JournalJournal of Experimental Medicine
Volume210
Issue number2
DOIs
StatePublished - Feb 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Kannan, S., Sutphin, R. M., Hall, M. G., Golfman, L. S., Fang, W., Nolo, R. M., Akers, L. J., Hammitt, R. A., McMurray, J. S., Kornblau, S. M., Melnick, A. M., Figueroa, M. E., & Zweidler-McKay, P. A. (2013). Notch activation inhibits AML growth and survival: A potential therapeutic approach. Journal of Experimental Medicine, 210(2), 321-337. https://doi.org/10.1084/jem.20121527