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

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 a...

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Autores principales: Kannan, 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., Zweidler-McKay, Patrick A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570106/
https://www.ncbi.nlm.nih.gov/pubmed/23359069
http://dx.doi.org/10.1084/jem.20121527
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author Kannan, 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.
Zweidler-McKay, Patrick A.
author_facet Kannan, 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.
Zweidler-McKay, Patrick A.
author_sort Kannan, Sankaranarayanan
collection PubMed
description 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.
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spelling pubmed-35701062013-08-11 Notch activation inhibits AML growth and survival: a potential therapeutic approach Kannan, 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. Zweidler-McKay, Patrick A. J Exp Med Article 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. The Rockefeller University Press 2013-02-11 /pmc/articles/PMC3570106/ /pubmed/23359069 http://dx.doi.org/10.1084/jem.20121527 Text en © 2013 Kannan et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Kannan, 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.
Zweidler-McKay, Patrick A.
Notch activation inhibits AML growth and survival: a potential therapeutic approach
title Notch activation inhibits AML growth and survival: a potential therapeutic approach
title_full Notch activation inhibits AML growth and survival: a potential therapeutic approach
title_fullStr Notch activation inhibits AML growth and survival: a potential therapeutic approach
title_full_unstemmed Notch activation inhibits AML growth and survival: a potential therapeutic approach
title_short Notch activation inhibits AML growth and survival: a potential therapeutic approach
title_sort notch activation inhibits aml growth and survival: a potential therapeutic approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570106/
https://www.ncbi.nlm.nih.gov/pubmed/23359069
http://dx.doi.org/10.1084/jem.20121527
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