Notch pathway activation targets AML-initiating cell homeostasis and differentiation
Camille Lobry,Panagiotis Ntziachristos,Delphine Ndiaye-Lobry,Philmo Oh,Luisa Cimmino,Nan Zhu,Elisa Araldi,Wenhuo Hu,Jacquelyn Freund,Omar Abdel-Wahab,Sherif Ibrahim,Dimitris Skokos,Scott A. Armstrong,Ross L. Levine,Christopher Y. Park,Iannis Aifantis +15 more
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TLDR
Notch behaves as a tumor suppressor in AML, and Notch activation induces cell cycle arrest, differentiation, and apoptosis of AML-initiating cells.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.read more
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Journal ArticleDOI
Role of TET enzymes in DNA methylation, development, and cancer
TL;DR: Recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription are highlighted and some of the key outstanding questions are discussed.
Journal ArticleDOI
Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts
Aruna Kode,John S. Manavalan,Ioanna Mosialou,Govind Bhagat,Chozha V. Rathinam,Na Luo,Hossein Khiabanian,Albert Lee,Vundavalli V. Murty,Richard A. Friedman,Andrea Brum,David C. Park,Naomi Galili,Siddhartha Mukherjee,Julie Teruya-Feldstein,Azra Raza,Raul Rabadan,Ellin Berman,Stavroula Kousteni +18 more
TL;DR: It is demonstrated that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acuteMyeloidLeukaemia.
Journal ArticleDOI
Therapeutic modulation of Notch signalling — are we there yet?
Emma R. Andersson,Urban Lendahl +1 more
TL;DR: This Review focuses on aspects of the Notch signalling pathway that are amenable to therapeutic intervention, diseases that could be targeted and the various Notch pathway modulation strategies that are currently being explored.
Journal ArticleDOI
Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies.
TL;DR: The clinical manifestations of CH, mechanisms contributing to its development, the role of CH in clonal evolution toward leukemia, and the contribution of CH to non-hematological disease states are discussed.
Journal ArticleDOI
From Fly Wings to Targeted Cancer Therapies: A Centennial for Notch Signaling
TL;DR: The protumorigenic and tumor-suppressive functions of Notch signaling are discussed, and the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors are dissected.
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