Notch pathway activation targets AML-initiating cell homeostasis and differentiation. J Exp Med 2013 Feb 11;210(2):301-19
Date
01/30/2013Pubmed ID
23359070Pubmed Central ID
PMC3570103DOI
10.1084/jem.20121484Scopus ID
2-s2.0-84874580514 (requires institutional sign-in at Scopus site) 137 CitationsAbstract
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.
Author List
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 SA, Levine RL, Park CY, Aifantis IMESH terms used to index this publication - Major topics in bold
AnimalsCell Differentiation
Cell Survival
DNA-Binding Proteins
Dioxygenases
Disease Models, Animal
Gene Silencing
Homeostasis
Humans
Leukemia, Myeloid, Acute
Ligands
Mice
Mice, Transgenic
Mutation
Proto-Oncogene Proteins
Receptors, Notch
Signal Transduction
Tumor Suppressor Proteins
