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Notch pathway activation targets AML-initiating cell homeostasis and differentiation. J Exp Med 2013 Feb 11;210(2):301-19

Date

01/30/2013

Pubmed ID

23359070

Pubmed Central ID

PMC3570103

DOI

10.1084/jem.20121484

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.

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 I

Author

Nan Zhu PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Differentiation
Cell Survival
DNA-Binding Proteins
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
jenkins-FCD Prod-411 e00897e83867fcfa48419861683711f8d99adb75