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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
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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.
Journal of Experimental Medicine 01/2013; · 13.85 Impact Factor
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Catherine M Sawai,
Jacquelyn Freund, Philmo Oh,
Delphine Ndiaye-Lobry,
Jamieson C Bretz,
Alexandros Strikoudis,
Lali Genesca,
Thomas Trimarchi,
Michelle A Kelliher,
Marcus Clark,
Jean Soulier,
Selina Chen-Kiang,
Iannis Aifantis
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ABSTRACT: D-type cyclins form complexes with cyclin-dependent kinases (CDK4/6) and promote cell cycle progression. Although cyclin D functions appear largely tissue specific, we demonstrate that cyclin D3 has unique functions in lymphocyte development and cannot be replaced by cyclin D2, which is also expressed during blood differentiation. We show that only combined deletion of p27(Kip1) and retinoblastoma tumor suppressor (Rb) is sufficient to rescue the development of Ccnd3(-/-) thymocytes. Furthermore, we show that a small molecule targeting the kinase function of cyclin D3:CDK4/6 inhibits both cell cycle entry in human T cell acute lymphoblastic leukemia (T-ALL) and disease progression in animal models of T-ALL. These studies identify unique functions for cyclin D3:CDK4/6 complexes and suggest potential therapeutic protocols for this devastating blood tumor.
Cancer cell 10/2012; 22(4):452-65. · 25.29 Impact Factor
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ABSTRACT: Notch signaling is often considered a model hematopoietic proto-oncogene because of its role as the main trigger of T cell acute lymphoblastic leukemia (T-ALL). Although its role in T-ALL is well characterized and further supported by a high frequency of activating NOTCH1 mutations in T-ALL patients, it still remains an open question whether the effects of Notch signaling are causative in other types of cancer, including solid tumors. Growing evidence supported by recent studies unexpectedly shows that Notch signaling can also have a potent tumor suppressor function in both solid tumors and hematological malignancies. We discuss the intriguing possibility that the pleiotropic functions of Notch can be tumor suppressive or oncogenic depending on the cellular context.
Journal of Experimental Medicine 09/2011; 208(10):1931-5. · 13.85 Impact Factor
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Apostolos Klinakis,
Camille Lobry,
Omar Abdel-Wahab, Philmo Oh,
Hiroshi Haeno,
Silvia Buonamici,
Inge van De Walle,
Severine Cathelin,
Thomas Trimarchi,
Elisa Araldi,
Cynthia Liu,
Sherif Ibrahim,
Miroslav Beran,
Jiri Zavadil,
Argiris Efstratiadis,
Tom Taghon,
Franziska Michor,
Ross L Levine,
Iannis Aifantis
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ABSTRACT: Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types. Its activity is controlled by the multi-subunit γ-secretase (γSE) complex. Although Notch signalling can play both oncogenic and tumour-suppressor roles in solid tumours, in the haematopoietic system it is exclusively oncogenic, notably in T-cell acute lymphoblastic leukaemia, a disease characterized by Notch1-activating mutations. Here we identify novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukaemia (CMML). Inactivation of Notch signalling in mouse haematopoietic stem cells (HSCs) results in an aberrant accumulation of granulocyte/monocyte progenitors (GMPs), extramedullary haematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signalling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Our studies identify a novel role for Notch signalling during early haematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumour-promoting and -suppressive roles within the same tissue.
Nature 05/2011; 473(7346):230-3. · 36.28 Impact Factor
