TY - JOUR
T1 - Notch pathway activation targets AML-initiating cell homeostasis and differentiation
AU - Lobry, Camille
AU - Ntziachristos, Panagiotis
AU - Ndiaye-Lobry, Delphine
AU - Oh, Philmo
AU - Cimmino, Luisa
AU - Zhu, Nan
AU - Araldi, Elisa
AU - Hu, Wenhuo
AU - Freund, Jacquelyn
AU - Abdel-Wahab, Omar
AU - Ibrahim, Sherif
AU - Skokos, Dimitris
AU - Armstrong, Scott A.
AU - Levine, Ross L.
AU - Park, Christopher Y.
AU - Aifantis, Iannis
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20121484
DO - 10.1084/jem.20121484
M3 - Article
C2 - 23359070
AN - SCOPUS:84874580514
VL - 210
SP - 301
EP - 319
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 2
ER -