T cell acute lymphoblastic leukemia (T-ALL) is a disease induced by transformation of hematopoietic stem cells/progenitors. It afflicts mainly children and adolescents. Although treatment outcome in T-ALL has improved in recent years, patients with relapsed disease continue to have dismal prognosis. It is thus very important to identify and study the molecular pathways that control both induction of transformation and treatment resistance in this particular type of leukemia. Recent evidence demonstrated that activating mutations in the Notch1 oncogene are the trigger for cell transformation in the majority of T-ALL patients. The majority of the T-ALL Notch1 mutations are truncating a portion of the Notch1 protein called the PEST domain. Although this domain has been previously suggested to be important for Notch1 proteasome-mediated degradation, the exact mechanism of regulation of Notch1 stability and its role in T cell transformation and human T-ALL is currently unknown. We present here a large amount of experimental evidence that identifies the E3 ubiquitin ligase Fbw7 as an important regulator of Notch1 protein stability, through its interaction with a Threonine-centered degron sequence situated in the Notch1 PEST domain. We also demonstrate that T-ALL- inducing Notch1 mutations target this Fbw7 degron and that the Fbw7 gene itself is mutated and inactivated in a significant portion of human T-ALL. These and other preliminary observations presented in our application make us hypothesize that Fbw7 is an important novel tumor suppressor in T cell leukemia and its inactivation can trigger T cell transformation due to the stabilization of essential Fbw7 substrates. In this application we initially test the importance of the Notch1: Fbw7 interaction in leukemia by generating "knock-in" mice that lack the essential degron on the Notch1 PEST domain. Moreover, to directly prove that Fbw7 is a tumor suppressor in T-ALL we generate conditional, T-cell specific Fbw7 knock-out mice and study the effect of the deficiency in T cell transformation and development. Moreover, using these genetic tools we identify the essential downstream targets of Fbw7 in T cell transformation. Finally, we study both in vitro and in vivo the effect of Fbw7 mutations on gamma-secretase inhibitor treatment of T-ALL.
T cell acute lymphoblastic leukemia (T-ALL) is a disease induced by malignant transformation of T lymphocytes. Although treatment outcome of T-ALL has improved in recent years, patients with relapsed disease continue to have dismal prognosis. In an attempt to identify and study the molecular pathways that control T cell transformation we study here the interplay between Notch1, an oncogene mutated in the majority of T- ALL patients, and Fbw7, a ubiquitin ligase that can ubiquitinate and degrade nuclear, oncogenic Notch1.
|Ntziachristos, Panagiotis; Lim, Jing Shan; Sage, Julien et al. (2014) From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell 25:318-34|
|Rustighi, Alessandra; Zannini, Alessandro; Tiberi, Luca et al. (2014) Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast. EMBO Mol Med 6:99-119|
|Gough, Daniel J; Marié, Isabelle J; Lobry, Camille et al. (2014) STAT3 supports experimental K-RasG12D-induced murine myeloproliferative neoplasms dependent on serine phosphorylation. Blood 124:2252-61|
|Trimarchi, Thomas; Bilal, Erhan; Ntziachristos, Panagiotis et al. (2014) Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell 158:593-606|
|Strikoudis, Alexandros; Guillamot, Maria; Aifantis, Iannis (2014) Regulation of stem cell function by protein ubiquitylation. EMBO Rep 15:365-82|
|Lobry, Camille; Oh, Philmo; Mansour, Marc R et al. (2014) Notch signaling: switching an oncogene to a tumor suppressor. Blood 123:2451-9|
|Ntziachristos, Panagiotis; Tsirigos, Aristotelis; Welstead, G Grant et al. (2014) Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514:513-7|
|Di Micco, Raffaella; Fontanals-Cirera, Barbara; Low, Vivien et al. (2014) Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Rep 9:234-47|
|Reavie, Linsey; Buckley, Shannon M; Loizou, Evangelia et al. (2013) Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell 23:362-75|
|Ntziachristos, Panagiotis; Mullenders, Jasper; Trimarchi, Thomas et al. (2013) Mechanisms of epigenetic regulation of leukemia onset and progression. Adv Immunol 117:1-38|
Showing the most recent 10 out of 32 publications