Combined expression of pTα and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis

Bellavia, Diana; Campese, Antonio Francesco; Checquolo, Saula; Balestri, Anna; Biondi, Andrea; Cazzaniga, Giovanni; Lendahl, Urban; Fehling, Hans Jörg; Hayday, Adrian; Frati, Luigi; Boehmer, Harald von; Gulino, Alberto; Screpanti, Isabella

doi:10.1073/pnas.062050599

Cited by 189 publications

(244 citation statements)

References 31 publications

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“…Retroviral oncogenesis in mice indicates a synergistic interaction between Notch1 and c-myc [162], E2A/ pbx [163] and dominant negative forms of Ikaros [164] to enhance development of T-ALL. Apart from Notch1, Notch3 was consistently expressed in human T-ALL and dramatically reduced in clinical remission [165]. It was shown by the Screpanti group that Notch target genes Hes1 and preTa are associated with Notch3 expression.…”

Section: Notch and Leukemiamentioning

confidence: 99%

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Borggrefe

Oswald

2009

Cell. Mol. Life Sci.

584

499

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. The Notch gene encodes a transmembrane receptor that gave the name to the evolutionary highly conserved Notch signaling cascade. It plays a pivotal role in the regulation of many fundamental cellular processes such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. After specific ligand binding, the intracellular part of the Notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor RBP-J. In the absence of activated Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. Here, we review Notch signaling with a focus on gene regulatory events at Notch target genes. This is of utmost importance to understand Notch signaling since certain RBP-J associated cofactors and particular epigenetic marks determine the specificity of Notch target gene expression in different cell types. We subsequently summarize the current knowledge about Notch target genes and the physiological significance of Notch signaling in development and cancer.

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Section: Notch and Leukemiamentioning

confidence: 99%

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Borggrefe

Oswald

2009

Cell. Mol. Life Sci.

584

499

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“…Nevertheless, the molecular mechanisms priming and/or regulating Notch signaling remain undefined. Although Notch3 transgenic mice recapitulate cellular and molecular features of T-ALL and Notch3 overexpression was observed in virtually all patients with T-ALL (Bellavia et al, 2002), gene mutations or evident gene rearrangements of Notch3 have never been observed, diversely from what happens for Notch1 (Weng et al, 2004). Altered degradation process may be responsible for protein overexpression, however, no data are available, as yet, addressing the mechanisms regulating Notch3 processing/degradation, whose deregulation may be responsible of its increased expression in leukemic cells and susceptible to become therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

“…Members of the Notch family (for example, Notch1 and Notch3) have been described to have a critical role in T-cell development (Deftos et al, 1998(Deftos et al, , 2000Rothenberg, 2001;Campese et al, 2003) and their constitutive activation has been related to T-cell leukemia development in both animals models (Pear et al, 1996;Bellavia et al, 2000) and human disease (Ellisen et al, 1991;Bellavia et al, 2002). Our previous findings have suggested a specific role for Notch3 receptor at the pre-T-cell receptor (pre-TCR) checkpoint of intrathymic T-cell differentiation process, resulting in the development of acute T-cell leukemia in Notch3-IC transgenic (tg N3-IC) mice (Bellavia et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Our previous findings have suggested a specific role for Notch3 receptor at the pre-T-cell receptor (pre-TCR) checkpoint of intrathymic T-cell differentiation process, resulting in the development of acute T-cell leukemia in Notch3-IC transgenic (tg N3-IC) mice (Bellavia et al, 2000). We then showed that the combined overexpression of Notch3 and pTa characterizes T-cell acute lymphoblastic leukemia (T-ALL) and that deletion of pTa gene is able to abrogate this leukemogenic process (Bellavia et al, 2002). However, the molecular mechanisms sustaining Notch3 protein overexpression and the relationships between Notch3 and pTa remain undefined.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that Notch3 and pTa signaling events are essential for Notch3-mediated T-cell leukemogenesis (Bellavia et al, 2002;Talora et al, 2006). To assess whether pTa has a role in regulating the c-Cbl-dependent degradation of Notch3, we cotransfected HEK293 cells with N3-IC and c-Cbl in the presence or absence of pTa.…”

Section: Introductionmentioning

confidence: 99%

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Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia

et al. 2009

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Notch3 and pT alpha signaling events are essential for T-cell leukemogenesis and characterize murine and human T-cell acute lymphoblastic leukemia. Genetic ablation of pT alpha expression in Notch3 transgenic mice abrogates tumor development, indicating that pT alpha signaling is crucial to the Notch3-mediated leukemogenesis. Here we report a novel direct interaction between Notch3 and pT alpha. This interaction leads to the recruitment and persistence of the E3 ligase protein c-Cbl to the lipid rafts in Notch3-IC transgenic thymocytes. Conversely, deletion of pT alpha in Notch3 transgenic mice leads to cytoplasmic retention of c-Cbl that targets Notch3 protein to the proteasomal-degradative pathway. It appears that protein kinase C theta (PKC theta), by regulating tyrosine and serine phosphorylation of Cbl, is able to control its function. We report here that the increased Notch3-IC degradation correlates with higher levels of c-Cbl tyrosine phosphorylation in Notch3-IC/pT alpha(-/-) double-mutant thymocytes, which also display a decreased PKC theta activity. Our data indicate that pT alpha/pre-T-cell receptor is able to regulate the different subcellular localization of c-Cbl and, by regulating PKC theta activity, is also able to influence its ubiquitin ligase activity upon Notch3 protein. Oncogene (2010) 29, 1463-1474; doi:10.1038/onc.2009.446; published online 7 December 200

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Unexpected features of acute T lymphoblastic lymphomas in Notch1IC transgenic rats

et al. 2006

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Dysregulated Notch signaling accounts for the majority of acute T lymphoblastic leukemia/lymphoma (T-ALL) cases in humans. Here, we characterize lymphomas from Notch1IC transgenic rats, which develop T-ALL shortly after weaning, and show that they display a number of previously undocumented features. Starting from monoclonal thymic tumors, the CD4(+)CD8alphaalpha(+) lymphoma cells infiltrate the bone marrow and then spread to secondary lymphoid and non-lymphoid organs. However, major hallmarks of T-ALL cells in other murine models and human patients, such as constitutive NF-kappaB activity and increased levels of anti-apoptotic proteins, are remarkably absent in Notch1IC lymphomas. In contrast, CD30, a classic marker of Hodgkin lymphomas, is overexpressed in these tumors. Intriguingly, enforced Notch1 signaling up-regulates expression of Notch3, which has also been implicated in the pathogenesis of T-ALL. By blocking endogenous Notch signaling, we could demonstrate that Notch1IC is sufficient to induce sustained preTCR expression in transgenic thymocytes but not for their progression to the double-positive stage. This suggests that other Notch activities may also contribute to the phenotype of the transgenic rats. In summary, we anticipate this new animal model will help to further elucidate the role of Notch1 in the pathogenesis of T-ALL.

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Combined expression of pTα and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis

Cited by 189 publications

References 31 publications

The Notch signaling pathway: Transcriptional regulation at Notch target genes

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia

Unexpected features of acute T lymphoblastic lymphomas in Notch1IC transgenic rats

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