期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 210, 期 2, 页码 301-319出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20121484
关键词
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资金
- National Institutes of Health [NIH]/National Cancer Institute [NCI] [P30 CA016087-30]
- NIH/NCI [5 P30CA16087-31]
- NYU Histology Core [5P30CA16087-31]
- Transgenic Mouse Core [5P30CA16087-31]
- NIH [RO1CA133379, RO1CA105129, R21CA141399, RO1CA149655, RO1GM088847]
- Leukemia & Lymphoma Society
- V Foundation for Cancer Research
- St. Baldrick's Foundation for Cancer Research
- Irma T. Hirschl Trust
- NYU Kimmel Stem Cell Institute
- Lady Tata Foundation
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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