Notch Signaling in Leukemias and Lymphomas

Jundt, Franziska; Schwarzer, Rolf; Dörken, Bernd

doi:10.2174/156652408783565540

Cited by 49 publications

(39 citation statements)

References 108 publications

(168 reference statements)

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“…The primer sequences were as follows: no. 1, AGT CAG ATC CTA GCG TCG AG (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33); no. 2, GGA GTA CGT GCA AGT CAC AG (381-362); no.…”

Section: Rna Analysesmentioning

confidence: 99%

“…21 For the purpose of our present study, it is also of particular interest that Notch family members contribute to the maintenance, renewal, and maturation of normal hematopoietic system, 22 and have been implicated in the promotion of different types of cancer, including hematologic malignancies. [23][24][25][26][27] On these bases, the aim of the present study was to evaluate the effect of Nutlin-3 treatment on Notch1 expression in both myeloid and lymphoid leukemic cell lines as well as in primary B-CLL cells and the role of Notch signaling in modulating Nutlin-3 cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism

Secchiero

Melloni

Iasio

et al. 2009

Blood

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The small molecule inhibitor of the MDM2/ p53 interaction Nutlin-3 significantly upregulated the steady-state mRNA and protein levels of Notch1 in TP53 wild-type (OCI, SKW6.4) but not in TP53 deleted (HL-60) or TP53 mutated (BJAB) leukemic cell lines. A direct demonstration that NOTCH1 was a transcriptional target of p53 in leukemic cells was obtained in experiments carried out with siRNA for p53. Moreover, inhibition of Notch1 expression using Notch1-specific siRNA significantly increased cytotoxicity in TP53 wild-type leukemic cells. IntroductionThe activation of p53 is tightly regulated by the human homolog of murine double minute 2 (MDM2) gene, 1 which is an E3 ubiquitin ligase for p53 and itself and controls p53 half-life mainly via ubiquitindependent degradation. In response to a variety of stimuli, such as cellular stress, the p53-MDM2 interaction is disrupted and p53 rapidly accumulates within the cell. 1 Potent and selective small molecule inhibitors of the p53-MDM2 interaction, the Nutlins, have been recently reported. 2,3 These compounds bind MDM2 in the p53 binding pocket with high selectivity and can release p53 from negative control, leading to effective stabilization of p53 and activation of the p53 pathway. 2,3 It has been demonstrated that treatment with the active enantiomer Nutlin-3a results in rising levels of p53 protein and subsequent induction of cell cycle arrest and apoptosis in a variety of tumor cells. 2 In contrast to most solid tumors, TP53 is mutated in approximately 10% to 15% of both myeloid and lymphoid leukemias at diagnosis, 4 and several recent studies have demonstrated that Nutlin-3 induces ex vivo cytotoxic cell death of most TP53 wild-type primary hematologic malignancies, including acute myeloid leukemias, multiple myeloma, B-chronic lymphocytic leukemias (B-CLL), and B-cell lymphomas. [5][6][7][8][9][10][11][12][13][14][15] Although it is well established that p53 mediates a variety of cellular functions, such as cell cycle arrest, cellular senescence, and, only as ultimate choice, apoptosis, 16,17 some experimental evidence suggests that inhibition of the transcriptional activity of p53 might paradoxically result in an increase of the p53-mediated proapoptotic activity, 18 also in B-CLL cells. 19 Therefore, the aim of this study was to further investigate the relationship between the transcriptional and cytotoxic activities induced by Nutlin-3 and to elucidate whether Nutlin-3 promotes the transcription of antiapoptotic genes in leukemic cells, which might hamper and/or reduce its potential therapeutic efficacy. In this respect, it has recently emerged that a potential target gene of the p53 pathway is NOTCH1, 20 which belongs to an evolutionarily conserved pathway that profoundly impacts mammalian development. Of note, a recent study published while this article was under preparation has demonstrated that circulating B-CLL cells overexpress Notch1 and Notch2 family members with respect to circulating normal B lymphocytes. 21 The same study suggested that constitutively...

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Section: Rna Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism

Secchiero

Melloni

Iasio

et al. 2009

Blood

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“…Dysfunction within the Notch signal transduction machinery characterizes developmental and malignant conditions, including lymphoid and myeloid leukemias (2,4,5,18,24,36). The four Notch receptors in vertebrates are type I transmembrane proteins that undergo complex posttranslational processing en route to the plasma membrane (7,14,51).…”

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confidence: 99%

Myeloid Translocation Gene 16 (MTG16) Interacts with Notch Transcription Complex Components To Integrate Notch Signaling in Hematopoietic Cell Fate Specification

Engel

Nguyen²,

Mariotti³

et al. 2010

Molecular and Cellular Biology

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The Notch signaling pathway regulates gene expression programs to influence the specification of cell fate in diverse tissues. In response to ligand binding, the intracellular domain of the Notch receptor is cleaved by the ␥-secretase complex and then translocates to the nucleus. There, it binds the transcriptional repressor CSL, triggering its conversion to an activator of Notch target gene expression. The events that control this conversion are poorly understood. We show that the transcriptional corepressor, MTG16, interacts with both CSL and the intracellular domains of Notch receptors, suggesting a pivotal role in regulation of the Notch transcription complex. The Notch1 intracellular domain disrupts the MTG16-CSL interaction. Ex vivo fate specification in response to Notch signal activation is impaired in Mtg16 ؊/؊ hematopoietic progenitors, and restored by MTG16 expression. An MTG16 derivative lacking the binding site for the intracellular domain of Notch1 fails to restore Notch-dependent cell fate. These data suggest that MTG16 interfaces with critical components of the Notch transcription complex to affect Notch-dependent lineage allocation in hematopoiesis.

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“…Furthermore, activated NOTCH1 protein expression was more frequently detected in malignant ACTs. However, no activating mutations in the PEST region of the NOTCH1 gene (Weng et al 2004, Jundt et al 2008, Ferrando 2010, Fabbri et al 2011, Paganin & Ferrando 2011, Rossi et al 2012 were detected in ACCs. Of note, although gene expression of Notch1 pathway components correlated significantly in normal adrenals and adenomas, this relationship was lost in ACCs, which indicates dysregulation of Notch1 signaling in malignant tumors.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the translocation t(7;9)(q34;q34.3) or mutations in the NOTCH gene (including PEST truncating mutations), which lead to Notch-ligand independent activation or to impaired degradation of activated Notch, have been shown to play a role in T-cell acute lymphoblastic leukemia (Weng et al 2004, Jundt et al 2008, Ferrando 2010, Paganin & Ferrando 2011. In solid tumors, both oncogenic actions or a tumor suppressor role of the Notch signaling pathway and its components have been reported, depending on the cell type and context (Supplementary Table S1, see section on supplementary data given at the end of this article) (Radtke & Raj 2003, Balint et al 2005, Wang et al 2006, Westhoff et al 2009, Lobry et al 2011, Mazur et al 2012, Rizzo et al 2013, Carvalho et al 2014, Du et al 2014.…”

Section: Introductionmentioning

confidence: 99%

Notch1 pathway in adrenocortical carcinomas: correlations with clinical outcome

Ronchi¹,

Sbiera²,

Altieri³

et al. 2015

Endocrine-Related Cancer

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Previous SNP array analyses have revealed genomic alterations of the Notch pathway as being the most frequent abnormality in adrenocortical tumors (ACTs). The aim of the present study was to evaluate the expression of components of Notch signaling in ACTs and to correlate them with clinical outcome. The mRNA expression of JAG1, NOTCH1, and selected target genes of NOTCH1 (HES1, HES5, and HEY2) was evaluated in 80 fresh frozen samples (28 normal adrenal glands (NAGs), 24 adenomas (ACAs), and 28 carcinomas (ACCs)) by quantitative RT-PCR. Immunohistochemistry was performed in 221 tissues on paraffin slides (16 NAGs, 27 ACAs, and 178 ACCs) for JAG1, activated NOTCH1 (aNOTCH1), and HEY2. An independent ACC validation cohort (nZ77) was then also investigated. HEY2 mRNA expression was higher in ACCs than it was in ACAs (P!0.05). The protein expression of all of the factors was high (H-score 2-3) in a larger proportion of ACCs as compared to ACAs and NAGs (JAG1 in 27, 15, and 10%; aNOTCH1 in 13, 8, and 0%; HEY2 in 66, 61, and 33% respectively, all P!0.001). High JAG1 expression was associated with earlier tumor stages and lower numbers of metastases in ACCs (both PZ0.08) and favorably impacted overall and progression-free survival (PFS) (131 vs 30 months, hazard ratio (HR) 0.45, and 37 vs 9 months, HR 0.51, both P!0.005). This impact on overall survival (OS) was confirmed in the validation cohort. No such association was observed for aNOTCH1 or HEY2. In conclusion, different components of the Notch1 signaling pathway are overexpressed in ACCs, which suggests a role for the pathway in malignant transformation. However, JAG1 is overexpressed in a subgroup of ACCs with a better clinical outcome.

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Notch Signaling in Leukemias and Lymphomas

Cited by 49 publications

References 108 publications

Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism

Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism

Myeloid Translocation Gene 16 (MTG16) Interacts with Notch Transcription Complex Components To Integrate Notch Signaling in Hematopoietic Cell Fate Specification

Notch1 pathway in adrenocortical carcinomas: correlations with clinical outcome

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