Notch pathway activation targets AML-initiating cell homeostasis and differentiation Journal Article

   

Authors:	Lobry, C.; Ntziachristos, P.; Ndiaye-Lobry, D.; Oh, P.; Cimmino, L.; Zhu, N.; Araldi, E.; Hu, W.; Freund, J.; Abdel-Wahab, O.; Ibrahim, S.; Skokos, D.; Armstrong, S. A.; Levine, R. L.; Park, C. Y.; Aifantis, I.
Article Title:	Notch pathway activation targets AML-initiating cell homeostasis and differentiation
Abstract:	Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia. © 2013 Lobry et al.
Journal Title:	Journal of Experimental Medicine
Volume:	210
Issue:	2
ISSN:	0022-1007
Publisher:	Rockefeller University Press
Date Published:	2013-02-11
Start Page:	301
End Page:	319
Language:	English
DOI:	10.1084/jem.20121484
PROVIDER:	scopus
PMCID:	PMC3570103
PUBMED:	23359070
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84874580514&partnerID=40&md5=b6e79340d64ed8ff906a42038af4f5da
Notes:	--- - "Export Date: 1 April 2013" - "CODEN: JEMEA" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/38874