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NOTCH1; notch 1 (9q34.3)

Gene Summary

Gene:NOTCH1; notch 1
Aliases: hN1, TAN1
Location:9q34.3
Summary:This gene encodes a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between physically adjacent cells. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remain to be determined. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. This protein functions as a receptor for membrane bound ligands, and may play multiple roles during development. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:neurogenic locus notch homolog protein 1
HPRD
Source:NCBI
Updated:12 July, 2014

Gene
Ontology:

What does this gene/protein do?
NOTCH1 is implicated in:
- acrosomal vesicle
- aortic valve morphogenesis
- arterial endothelial cell differentiation
- astrocyte differentiation
- atrioventricular valve morphogenesis
- calcium ion binding
- cardiac atrium morphogenesis
- cardiac chamber formation
- cardiac epithelial to mesenchymal transition
- cardiac left ventricle morphogenesis
- cardiac muscle tissue morphogenesis
- cardiac right atrium morphogenesis
- cardiac septum morphogenesis
- cardiac vascular smooth muscle cell development
- cardiac ventricle morphogenesis
- cell differentiation in spinal cord
- cell migration involved in endocardial cushion formation
- cellular response to follicle-stimulating hormone stimulus
- collecting duct development
- core promoter binding
- coronary artery morphogenesis
- coronary vein morphogenesis
- determination of left/right symmetry
- distal tubule development
- endocardial cell differentiation
- endocardial cushion morphogenesis
- endocardium development
- endocardium morphogenesis
- endoplasmic reticulum membrane
- enzyme binding
- enzyme inhibitor activity
- epithelial to mesenchymal transition
- epithelial to mesenchymal transition involved in endocardial cushion formation
- extracellular region
- gene expression
- glomerular mesangial cell development
- Golgi membrane
- growth involved in heart morphogenesis
- heart development
- heart looping
- heart trabecula morphogenesis
- immune response
- integral to membrane
- MAML1-RBP-Jkappa- ICN1 complex
- mesenchymal cell development
- mitral valve formation
- negative regulation of anoikis
- negative regulation of BMP signaling pathway
- negative regulation of catalytic activity
- negative regulation of cell-substrate adhesion
- negative regulation of glial cell proliferation
- negative regulation of myoblast differentiation
- negative regulation of myotube differentiation
- negative regulation of neurogenesis
- negative regulation of neuron differentiation
- negative regulation of oligodendrocyte differentiation
- negative regulation of ossification
- negative regulation of osteoblast differentiation
- negative regulation of pro-B cell differentiation
- negative regulation of stem cell differentiation
- negative regulation of transcription from RNA polymerase II promoter
- negative regulation of transcription, DNA-dependent
- neuronal stem cell maintenance
- Notch receptor processing
- Notch signaling involved in heart development
- Notch signaling pathway
- nucleoplasm
- nucleus
- oligodendrocyte differentiation
- organ regeneration
- pericardium morphogenesis
- plasma membrane
- positive regulation of astrocyte differentiation
- positive regulation of BMP signaling pathway
- positive regulation of cardiac muscle cell proliferation
- positive regulation of cell migration
- positive regulation of cell proliferation
- positive regulation of endothelial cell differentiation
- positive regulation of epithelial to mesenchymal transition
- positive regulation of JAK-STAT cascade
- positive regulation of neuroblast proliferation
- positive regulation of transcription from RNA polymerase II promoter
- positive regulation of transcription from RNA polymerase II promoter in response to hypoxia
- positive regulation of transcription of Notch receptor target
- positive regulation of transcription, DNA-dependent
- protein binding
- pulmonary valve morphogenesis
- receptor activity
- regulation of cardioblast proliferation
- regulation of extracellular matrix assembly
- regulation of transcription from RNA polymerase II promoter involved in myocardial precursor cell differentiation
- regulation of transcription, DNA-dependent
- response to corticosteroid stimulus
- response to lipopolysaccharide
- response to muramyl dipeptide
- RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription
- sequence-specific DNA binding transcription factor activity
- spermatogenesis
- tissue regeneration
- transcription initiation from RNA polymerase II promoter
- vasculogenesis involved in coronary vascular morphogenesis
- venous endothelial cell differentiation
- ventricular septum morphogenesis
- ventricular trabecula myocardium morphogenesis
Data from Gene Ontology via CGAP

Pathways:

What pathways are this gene/protein implicaed in?
- Presenilin action in Notch and Wnt signaling BIOCARTA
- Proteolysis and Signaling Pathway of Notch BIOCARTA
- Segmentation Clock BIOCARTA
- Dorso-ventral axis formation KEGG
- Notch signaling pathway KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 12 July 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 12 July, 2014 using data from PubMed, MeSH and CancerIndex

Notable

NOTCH1 and Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Related Publications (100)

NOTCH1 and Breast Cancer

Related Publications (90)

NOTCH1 and Childhood T-Cell ALL

Related Publications (67)

NOTCH1 mutations in Head and Neck Cancers
Agrawal et al (2011) whole-exome sequencing and gene copy number analyses to study 32 primary hesd and neck squamous cell tumors and found that nearly 40% of 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in HNSCC.
Related Publications (66)

NOTCH1 and Chronic Lymphocytic Leukemia

Related Publications (64)

NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL)
"T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy of thymocytes affecting preferentially children and adolescents. The disease is heterogeneous and characterized by a large set of chromosomal and genetic alterations that deregulate the growth of maturing thymocytes. The identification of activating point mutations in NOTCH1 in more then 50% of all T-ALL cases highlights the NOTCH1 cascade as a central player of T-ALL pathogenesis." (Koch et al, 2011)
Related Publications (39)

NOTCH1 / Notch signaling and Drug Resistance
Notch signaling and NOTCH1 expression has been implicated in drug resistance in a number of studies.
Related Publications (23)

NOTCH1 and Thyroid Cancer

Related Publications (12)

t(7;9)(q34;q34) in T-Cell Acute Lymphoblastic Leukaemia

Related Publications (7)

Related Links

Latest Publications: NOTCH1 (cancer-related)

Aydin IT, Melamed RD, Adams SJ, et al.
FBXW7 mutations in melanoma and a new therapeutic paradigm.
J Natl Cancer Inst. 2014; 106(6):dju107 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: Melanoma is a heterogeneous tumor with subgroups requiring distinct therapeutic strategies. Genetic dissection of melanoma subgroups and identification of therapeutic agents are of great interest in the field. These efforts will ultimately lead to treatment strategies, likely combinatorial, based on genetic information.
METHODS: To identify "driver" genes that can be targeted therapeutically, we screened metastatic melanomas for somatic mutations by exome sequencing followed by selecting those with available targeted therapies directed to the gene product or its functional partner. The FBXW7 gene and its substrate NOTCH1 were identified and further examined. Mutation profiling of FBXW7, biological relevance of these mutations and its inactivation, and pharmacological inhibition of NOTCH1 were examined using in vitro and in vivo assays.
RESULTS: We found FBXW7 to be mutated in eight (8.1%) melanoma patients in our cohort (n = 103). Protein expression analysis in human tissue samples (n = 96) and melanoma cell lines (n = 20) showed FBXW7 inactivation as a common event in melanoma (40.0% of cell lines). As a result of FBXW7 loss, we observed an accumulation of its substrates, such as NOTCH1. Ectopic expression of mutant forms of FBXW7 (by 2.4-fold), as well as silencing of FBXW7 in immortalized melanocytes, accelerated tumor formation in vivo (by 3.9-fold). Its inactivation led to NOTCH1 activation, upregulation of NOTCH1 target genes (by 2.6-fold), and promotion of tumor angiogenesis and resulted in tumor shrinkage upon NOTCH1 inhibition (by fivefold).
CONCLUSIONS: Our data provides evidence on FBXW7 as a critical tumor suppressor mutated and inactivated in melanoma that results in sustained NOTCH1 activation and renders NOTCH signaling inhibition as a promising therapeutic strategy in this setting.

Related: Melanoma Signal Transduction Skin Cancer FBXW7 gene


Martins VC, Busch K, Juraeva D, et al.
Cell competition is a tumour suppressor mechanism in the thymus.
Nature. 2014; 509(7501):465-70 [PubMed] Related Publications
Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between 'young' bone-marrow-derived and 'old' thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors.


Curry JM, Sprandio J, Cognetti D, et al.
Tumor microenvironment in head and neck squamous cell carcinoma.
Semin Oncol. 2014; 41(2):217-34 [PubMed] Related Publications
The tumor microenvironment (TME) of head and neck squamous cell carcinoma (HNSCC) is comprised of cancer-associated fibroblasts (CAFs), immune cells, and other supporting cells. Genetic changes in the carcinoma cells, such as alterations to TP53, NOTCH1, and specific gene expression profiles, contribute to derangements in cancer and microenvironment cells such as increased ROS, overproduction of cytokines, and epithelial to mesenchymal transition (EMT). CAFs are among the most critical elements of the TME contributing to proliferation, invasion, and metastasis. The adaptive immune response is suppressed in HNSCC through overexpression of cytokines, triggered apoptosis of T cells, and alterations in antigen processing machinery. Overexpression of critical cytokines, such as transforming growth factor-β (TGF-β), contributes to EMT, immune suppression, and evolution of CAFs. Inflammation and hypoxia are driving forces in angiogenesis and altered metabolism. HNSCC utilizes glycolytic and oxidative metabolism to fuel tumorigenesis via coupled mechanisms between cancer cell regions and cells of the TME. Increased understanding of the TME in HNSCC illustrates that the long-held notion of "condemned mucosa" reflects a process that extends beyond the epithelial cells to the entire tissue comprised of each of these elements.

Related: Cytokines Head and Neck Cancers Head and Neck Cancers - Molecular Biology Cancer Prevention and Risk Reduction


Brooks YS, Ostano P, Jo SH, et al.
Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer.
J Clin Invest. 2014; 124(5):2260-76 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
Downmodulation or loss-of-function mutations of the gene encoding NOTCH1 are associated with dysfunctional squamous cell differentiation and development of squamous cell carcinoma (SCC) in skin and internal organs. While NOTCH1 receptor activation has been well characterized, little is known about how NOTCH1 gene transcription is regulated. Using bioinformatics and functional screening approaches, we identified several regulators of the NOTCH1 gene in keratinocytes, with the transcription factors DLX5 and EGR3 and estrogen receptor β (ERβ) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ERβ controls NOTCH1 transcription through RNA PolII pause release. Expression of several identified NOTCH1 regulators, including ERβ, is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ERβ-dependent program of gene expression is subverted in SCCs from various body sites, and there are consistent differences in mutation and gene-expression signatures of head and neck and lung SCCs in female versus male patients. Experimentally increased ERβ expression or treatment with ERβ agonists inhibited proliferation of SCC cells and promoted NOTCH1 expression and squamous differentiation both in vitro and in mouse xenotransplants. Our data identify a link between transcriptional control of NOTCH1 expression and the estrogen response in keratinocytes, with implications for differentiation therapy of squamous cancer.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Lung Cancer


Treanor LM, Zhou S, Janke L, et al.
Interleukin-7 receptor mutants initiate early T cell precursor leukemia in murine thymocyte progenitors with multipotent potential.
J Exp Med. 2014; 211(4):701-13 [PubMed] Article available free on PMC after 07/10/2014 Related Publications
Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) exhibits lymphoid, myeloid, and stem cell features and is associated with a poor prognosis. Whole genome sequencing of human ETP-ALL cases has identified recurrent mutations in signaling, histone modification, and hematopoietic development genes but it remains to be determined which of these abnormalities are sufficient to initiate leukemia. We show that activating mutations in the interleukin-7 receptor identified in human pediatric ETP-ALL cases are sufficient to generate ETP-ALL in mice transplanted with primitive transduced thymocytes from p19(Arf-/-) mice. The cellular mechanism by which these mutant receptors induce ETP-ALL is the block of thymocyte differentiation at the double negative 2 stage at which myeloid lineage and T lymphocyte developmental potential coexist. Analyses of samples from pediatric ETP-ALL cases and our murine ETP-ALL model show uniformly high levels of LMO2 expression, very low to undetectable levels of BCL11B expression, and a relative lack of activating NOTCH1 mutations. We report that pharmacological blockade of Jak-Stat signaling with ruxolitinib has significant antileukemic activity in this ETP-ALL model. This new murine model recapitulates several important cellular and molecular features of ETP-ALL and should be useful to further define novel therapeutic approaches for this aggressive leukemia.

Related: Signal Transduction


Lin DC, Hao JJ, Nagata Y, et al.
Genomic and molecular characterization of esophageal squamous cell carcinoma.
Nat Genet. 2014; 46(5):467-73 [PubMed] Article available free on PMC after 01/11/2014 Related Publications
Esophageal squamous cell carcinoma (ESCC) is prevalent worldwide and particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified previously uncharacterized mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to those already known (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Our approaches also uncovered many druggable candidates, and XPO1 was further explored as a therapeutic target because it showed both gene mutation and protein overexpression. Our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets.

Related: Cancer of the Esophagus Esophageal Cancer FISH Signal Transduction


Song Y, Li L, Ou Y, et al.
Identification of genomic alterations in oesophageal squamous cell cancer.
Nature. 2014; 509(7498):91-5 [PubMed] Related Publications
Oesophageal cancer is one of the most aggressive cancers and is the sixth leading cause of cancer death worldwide. Approximately 70% of global oesophageal cancer cases occur in China, with oesophageal squamous cell carcinoma (ESCC) being the histopathological form in the vast majority of cases (>90%). Currently, there are limited clinical approaches for the early diagnosis and treatment of ESCC, resulting in a 10% five-year survival rate for patients. However, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we describe a comprehensive genomic analysis of 158 ESCC cases, as part of the International Cancer Genome Consortium research project. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases, plus an additional 70 ESCC cases not used in the whole-genome and whole-exome sequencing, were subjected to array comparative genomic hybridization analysis. We identified eight significantly mutated genes, of which six are well known tumour-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2), and two have not previously been described in ESCC (ADAM29 and FAM135B). Notably, FAM135B is identified as a novel cancer-implicated gene as assayed for its ability to promote malignancy of ESCC cells. Additionally, MIR548K, a microRNA encoded in the amplified 11q13.3-13.4 region, is characterized as a novel oncogene, and functional assays demonstrate that MIR548K enhances malignant phenotypes of ESCC cells. Moreover, we have found that several important histone regulator genes (MLL2 (also called KMT2D), ASH1L, MLL3 (KMT2C), SETD1B, CREBBP and EP300) are frequently altered in ESCC. Pathway assessment reveals that somatic aberrations are mainly involved in the Wnt, cell cycle and Notch pathways. Genomic analyses suggest that ESCC and head and neck squamous cell carcinoma share some common pathogenic mechanisms, and ESCC development is associated with alcohol drinking. This study has explored novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for ESCC.

Related: Chromosome 11 CGH Cancer of the Esophagus Esophageal Cancer


Knoechel B, Roderick JE, Williamson KE, et al.
An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia.
Nat Genet. 2014; 46(4):364-70 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
The identification of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL) led to clinical testing of γ-secretase inhibitors (GSIs) that prevent NOTCH1 activation. However, responses to these inhibitors have been transient, suggesting that resistance limits their clinical efficacy. Here we modeled T-ALL resistance, identifying GSI-tolerant 'persister' cells that expand in the absence of NOTCH1 signaling. Rare persisters are already present in naive T-ALL populations, and the reversibility of their phenotype suggests an epigenetic mechanism. Relative to GSI-sensitive cells, persister cells activate distinct signaling and transcriptional programs and exhibit chromatin compaction. A knockdown screen identified chromatin regulators essential for persister viability, including BRD4. BRD4 binds enhancers near critical T-ALL genes, including MYC and BCL2. The BRD4 inhibitor JQ1 downregulates expression of these targets and induces growth arrest and apoptosis in persister cells, at doses well tolerated by GSI-sensitive cells. Consistently, the GSI-JQ1 combination was found to be effective against primary human leukemias in vivo. Our findings establish a role for epigenetic heterogeneity in leukemia resistance that may be addressed by incorporating epigenetic modulators in combination therapy.

Related: Signal Transduction BRD4 gene


Lionetti M, Fabris S, Cutrona G, et al.
High-throughput sequencing for the identification of NOTCH1 mutations in early stage chronic lymphocytic leukaemia: biological and clinical implications.
Br J Haematol. 2014; 165(5):629-39 [PubMed] Related Publications
NOTCH1 mutations have recently emerged as new genetic lesions significantly correlated with survival in chronic lymphocytic leukaemia (CLL). We performed deep next generation sequencing of the NOTCH1 mutation hotspot in 384 cases at diagnosis, including 100 monoclonal B cell lymphocytosis (MBL) and 284 Binet stage A CLL cases, enrolled in the Gruppo Italiano Studio Linfomi O-CLL1 multicentre trial. The NOTCH1 c.7541_7542delCT dinucleotide deletion was detected and confirmed by an extremely sensitive polymerase chain reaction-based approach in 11% of MBL and 13·4% of CLL patients. Remarkably, the NOTCH1 mutation was often observed at low clonal level, mainly in MBL patients. Sequential analyses in a fraction of cases showed that the NOTCH1 mutation generally does not occur during the disease course and that the mutational load in positive cases tends to be stable over time. NOTCH1-mutated cases, even at low clonal level, displayed a significant reduction in median progression-free survival, although NOTCH1 mutation lost its prognostic impact in a multivariate analysis including 11q and/or 17p deletion, IGHV mutational status, and MBL or CLL status. Our data highlight the importance of using highly sensitive methods to measure NOTCH1 mutations, in order to improve prognostic stratification and obtain useful information for potential therapeutic approaches.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology


Messina M, Del Giudice I, Khiabanian H, et al.
Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness.
Blood. 2014; 123(15):2378-88 [PubMed] Article available free on PMC after 10/04/2015 Related Publications
Fludarabine refractoriness (FR) represents an unsolved clinical problem of chronic lymphocytic leukemia (CLL) management. Although next-generation sequencing studies have led to the identification of a number of genes frequently mutated in FR-CLL, a comprehensive evaluation of the FR-CLL genome has not been reported. Toward this end, we studied 10 FR-CLLs by combining whole-exome sequencing and copy number aberration (CNA) analysis, which showed an average of 16.3 somatic mutations and 4 CNAs per sample. Screening of recurrently mutated genes in 48 additional FR-CLLs revealed that ~70% of FR-CLLs carry ≥1 mutation in genes previously associated with CLL clinical course, including TP53 (27.5%), NOTCH1 (24.1%), SF3B1 (18.9%), and BIRC3 (15.5%). In addition, this analysis showed that 10.3% of FR-CLL cases display mutations of the FAT1 gene, which encodes for a cadherin-like protein that negatively regulates Wnt signaling, consistent with a tumor suppressor role. The frequency of FAT1-mutated cases was significantly higher in FR-CLL than in unselected CLLs at diagnosis (10.3% vs 1.1%, P = .004), suggesting a role in the development of a high-risk phenotype. These findings have general implications for the mechanisms leading to FR and point to Wnt signaling as a potential therapeutic target in FR-CLL.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology FAT1


Pastò A, Serafin V, Pilotto G, et al.
NOTCH3 signaling regulates MUSASHI-1 expression in metastatic colorectal cancer cells.
Cancer Res. 2014; 74(7):2106-18 [PubMed] Related Publications
MUSASHI-1 (MSI-1) is a well-established stem cell marker in both normal and malignant colon cells and it acts by positively regulating the NOTCH pathway through inactivation of NUMB, a NOTCH signaling repressor. To date, the mechanisms of regulation of MSI-1 levels remain largely unknown. Here, we investigated the regulation of MSI-1 by NOTCH signaling in colorectal cancer cell lines and in primary cultures of colorectal cancer metastases. Stimulation by the NOTCH ligand DLL4 was associated with an increase of MSI-1 mRNA and protein levels, and this phenomenon was prevented by the addition of an antibody neutralizing NOTCH2/3 but not NOTCH1. Moreover, forced expression of activated NOTCH3 increased MSI-1 levels, whereas silencing of NOTCH3 by short hairpin RNA reduced MSI-1 levels in both colorectal cancer cells and CRC tumor xenografts. Consistent with these findings, enforced NOTCH3 expression or stimulation by DLL4 increased levels of activated NOTCH1 in colorectal cell lines. Finally, treatment of colorectal cancer cells with anti-NOTCH2/3 antibody increased NUMB protein while significantly reducing formation of tumor cell spheroids. This novel feed-forward circuit involving DLL4, NOTCH3, MSI-1, NUMB, and NOTCH1 may be relevant for regulation of NOTCH signaling in physiologic processes as well as in tumor development. With regard to therapeutic implications, NOTCH3-specific drugs could represent a valuable strategy to limit NOTCH signaling in the context of colorectal cancers overexpressing this receptor.

Related: Colorectal (Bowel) Cancer Signal Transduction NOTCH3


Zhu Z, Todorova K, Lee KK, et al.
Small GTPase RhoE/Rnd3 is a critical regulator of Notch1 signaling.
Cancer Res. 2014; 74(7):2082-93 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Aberrations of Notch signaling have been implicated in a variety of human cancers. Oncogenic mutations in NOTCH1 are common in human T-cell leukemia and lymphomas. However, loss-of-function somatic mutations in NOTCH1 arising in solid tumors imply a tumor suppressor function, which highlights the need to understand Notch signaling more completely. Here, we describe the small GTPase RhoE/Rnd3 as a downstream mediator of Notch signaling in squamous cell carcinomas (SCC) that arise in skin epithelia. RhoE is a transcriptional target of activated Notch1, which is attenuated broadly in SCC cells. RhoE depletion suppresses Notch1-mediated signaling in vitro, rendering primary keratinocytes resistant to Notch1-mediated differentiation and thereby favoring a proliferative cell fate. Mechanistic investigations indicated that RhoE controls a key step in Notch1 signaling by mediating nuclear translocation of the activated portion of Notch1 (N1IC) through interaction with importins. Our results define RhoE as a Notch1 target that is essential for recruitment of N1IC to the promoters of Notch1 target genes, establishing a regulatory feedback loop in Notch1 signaling. This molecular circuitry may inform distinct cell fate decisions to Notch1 in epithelial tissues, where carcinomas such as SCC arise.

Related: Signal Transduction Skin Cancer


Gonzalez ME, Moore HM, Li X, et al.
EZH2 expands breast stem cells through activation of NOTCH1 signaling.
Proc Natl Acad Sci U S A. 2014; 111(8):3098-103 [PubMed] Article available free on PMC after 25/08/2014 Related Publications
Breast cancer is the second-leading cause of cancer-related deaths in women, but the details of how it begins remain elusive. Increasing evidence supports the association of aggressive triple-negative (TN) breast cancer with heightened expression of the Polycomb group protein Enhancer of Zeste Homolog 2 (EZH2) and increased tumor-initiating cells (TICs). However, mechanistic links between EZH2 and TICs are unclear, and direct demonstration of a tumorigenic function of EZH2 in vivo is lacking. Here, we identify an unrecognized EZH2/NOTCH1 axis that controls breast TICs in TN breast carcinomas. EZH2 overexpression increases NOTCH1 expression and signaling, and inhibition of NOTCH1 activity prevents EZH2-mediated stem cell expansion in nontumorigenic breast cells. We uncover a unique role of EZH2 in activating, rather than repressing, NOTCH1 signaling through binding to the NOTCH1 promoter in TN breast cancer cells. EZH2 binding is independent of its catalytic histone H3 lysine 27 methyltransferase activity and of the Polycomb Repressive Complex 2 but corresponds instead to transcriptional activation marks. In vivo, EZH2 knockdown decreases the onset and volume of xenografts derived from TN breast TICs. Conversely, transgenic EZH2 overexpression accelerates mammary tumor initiation and increases NOTCH1 activation in mouse mammary tumor virus-neu mice. Consonant with these findings, in clinical samples, high levels of EZH2 are significantly associated with activated NOTCH1 protein and increased TICs in TN invasive carcinomas. These data reveal a functional and mechanistic link between EZH2 levels, NOTCH1 signaling activation, and TICs, and provide previously unidentified evidence that EZH2 enhances breast cancer initiation.

Related: Signal Transduction


Ma J, Tang X, Wong P, et al.
Noncanonical activation of Notch1 protein by membrane type 1 matrix metalloproteinase (MT1-MMP) controls melanoma cell proliferation.
J Biol Chem. 2014; 289(12):8442-9 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
Notch1 is an evolutionarily conserved signaling molecule required for stem cell maintenance that is inappropriately reactivated in several cancers. We have previously shown that melanomas reactivate Notch1 and require its function for growth and survival. However, no Notch1-activating mutations have been observed in melanoma, suggesting the involvement of other activating mechanisms. Notch1 activation requires two cleavage steps: first by a protease and then by γ-secretase, which releases the active intracellular domain (Notch1(NIC)). Interestingly, although ADAM10 and -17 are generally accepted as the proteases responsible of Notch1 cleavage, here we show that MT1-MMP, a membrane-tethered matrix metalloproteinase involved in the pathogenesis of a number of tumors, is a novel protease required for the cleavage of Notch1 in melanoma cells. We find that active Notch1 and MT1-MMP expression correlate significantly in over 70% of melanoma tumors and 80% of melanoma cell lines, whereas such correlation does not exist between Notch1(NIC) and ADAM10 or -17. Modulation of MT1-MMP expression in melanoma cells affects Notch1 cleavage, whereas MT1-MMP expression in ADAM10/17 double knock-out fibroblasts restores the processing of Notch1, indicating that MT1-MMP is sufficient to promote Notch1 activation independently of the canonical proteases. Importantly, we find that MT1-MMP interacts with Notch1 at the cell membrane, supporting a potential direct cleavage mechanism of MT1-MMP on Notch1, and that MT1-MMP-dependent activation of Notch1 sustains melanoma cell growth. Together, the data highlight a novel mechanism of activation of Notch1 in melanoma cells and identify Notch1 as a new MT1-MMP substrate that plays important biological roles in melanoma.

Related: Melanoma


Gogoi D, Dar AA, Chiplunkar SV
Involvement of Notch in activation and effector functions of γδ T cells.
J Immunol. 2014; 192(5):2054-62 [PubMed] Related Publications
Notch signaling plays a pivotal role in cell fate decision and lineage commitment of lymphocytes. Although the role of Notch in CD4(+) and CD8(+) αβ T cells is well documented, there are no reports on how Notch signaling regulates effector functions of γδ T cells. γδ T cells are a minor fraction in the peripheral blood but are known to play a major role in defense against pathogens and tumors. In this study, we show that Notch receptors (mRNA and protein) are expressed in peripheral γδ T cells. Inhibition of Notch signaling by γ-secretase inhibitor inhibited the proliferation and IFN-γ secretion of γδ T cells in response to stimulation with phosphoantigens and anti-CD3 mAb. In the presence of γ-secretase inhibitor, the antitumor cytolytic ability of γδ T cells was inhibited with a decreased CD107a expression. Knockdown of Notch1 and Notch2 genes in γδ T cells using small interfering RNA inhibited their antitumor cytotoxic potential. Our study describes for the first time, to our knowledge, the role of Notch as an additional signal contributing to Ag-specific effector functions of γδ T cells.

Related: Cancer Prevention and Risk Reduction NOTCH2 gene Signal Transduction


Fogelstrand L, Staffas A, Wasslavik C, et al.
Prognostic implications of mutations in NOTCH1 and FBXW7 in childhood T-ALL treated according to the NOPHO ALL-1992 and ALL-2000 protocols.
Pediatr Blood Cancer. 2014; 61(3):424-30 [PubMed] Related Publications
BACKGROUND: In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.
PROCEDURE: We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.
RESULTS: Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P = 0.14) or event-free survival (EFS) (P = 0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.2 ± 1.9 (mean ± SEM), MYB 8.7 ± 0.8 (mean ± SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 ± 0.7, MYB 5.1 ± 1.2, P = 0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P = 0.02) and EFS (P = 0.028) was seen.
CONCLUSIONS: Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated.

Related: FBXW7 gene


Ross JS, Wang K, Rand JV, et al.
Comprehensive genomic profiling of relapsed and metastatic adenoid cystic carcinomas by next-generation sequencing reveals potential new routes to targeted therapies.
Am J Surg Pathol. 2014; 38(2):235-8 [PubMed] Related Publications
We hypothesized that next-generation sequencing could reveal actionable genomic alterations (GAs) and potentially expand treatment options for patients with advanced adenoid cystic carcinoma (ACC). Genomic profiling using next-generation sequencing was performed on hybridization-captured, adapter ligation libraries derived from 28 relapsed and metastatic formalin-fixed paraffin-embedded ACC. The 3230 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer were fully sequenced using the Illumina HiSeq 2000. All classes of GAs were evaluated. Actionable GAs were defined as those impacting targeted anticancer therapies on the market or in registered clinical trials. A total of 44 GAs were identified in the 28 ACC tumors, with 12 of 28 (42.9%) of tumors harboring at least 1 potentially actionable GA. The most common nonactionable GAs were identified in KD6MA (5 cases; 18%), ARID1A (4 cases; 14%), RUNX1 (2 cases; 7%), and MYC (2 cases; 7%). Actionable GAs included NOTCH1 (3 cases; 11%), MDM2 (2 cases; 7%), PDGFRA (2 cases; 7%), and CDKN2A/B (p16) (2 cases; 7%). Other potentially actionable GAs identified in a single case included: mutations in AKT1, BAP1, EGFR, and PIK3CA, homozygous deletion of FBXW7, and amplifications of CDK4, FGFR1, IGF1R, KDR, KIT, and MCL1. The frequency of GA in ACC is lower than that seen in the more common solid tumors. Comprehensive genomic profiling of ACC can identify actionable GAs in a subset of patients that could influence therapy for these difficult-to-treat progressive neoplasms.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology


Roderick JE, Tesell J, Shultz LD, et al.
c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells.
Blood. 2014; 123(7):1040-50 [PubMed] Article available free on PMC after 13/02/2015 Related Publications
Although prognosis has improved for children with T-cell acute lymphoblastic leukemia (T-ALL), 20% to 30% of patients undergo induction failure (IF) or relapse. Leukemia-initiating cells (LICs) are hypothesized to be resistant to chemotherapy and to mediate relapse. We and others have shown that Notch1 directly regulates c-Myc, a known regulator of quiescence in stem and progenitor populations, leading us to examine whether c-Myc inhibition results in efficient targeting of T-ALL-initiating cells. We demonstrate that c-Myc suppression by small hairpin RNA or pharmacologic approaches prevents leukemia initiation in mice by eliminating LIC activity. Consistent with its anti-LIC activity in mice, treatment with the BET bromodomain BRD4 inhibitor JQ1 reduces C-MYC expression and inhibits the growth of relapsed and IF pediatric T-ALL samples in vitro. These findings demonstrate a critical role for c-Myc in LIC maintenance and provide evidence that MYC inhibition may be an effective therapy for relapsed/IF T-ALL patients.


Sun W, Gaykalova DA, Ochs MF, et al.
Activation of the NOTCH pathway in head and neck cancer.
Cancer Res. 2014; 74(4):1091-104 [PubMed] Article available free on PMC after 15/02/2015 Related Publications
NOTCH1 mutations have been reported to occur in 10% to 15% of head and neck squamous cell carcinomas (HNSCC). To determine the significance of these mutations, we embarked upon a comprehensive study of NOTCH signaling in a cohort of 44 HNSCC tumors and 25 normal mucosal samples through a set of expression, copy number, methylation, and mutation analyses. Copy number increases were identified in NOTCH pathway genes, including the NOTCH ligand JAG1. Gene set analysis defined a differential expression of the NOTCH signaling pathway in HNSCC relative to normal tissues. Analysis of individual pathway-related genes revealed overexpression of ligands JAG1 and JAG2 and receptor NOTCH3. In 32% of the HNSCC examined, activation of the downstream NOTCH effectors HES1/HEY1 was documented. Notably, exomic sequencing identified 5 novel inactivating NOTCH1 mutations in 4 of the 37 tumors analyzed, with none of these tumors exhibiting HES1/HEY1 overexpression. Our results revealed a bimodal pattern of NOTCH pathway alterations in HNSCC, with a smaller subset exhibiting inactivating NOTCH1 receptor mutations but a larger subset exhibiting other NOTCH1 pathway alterations, including increases in expression or gene copy number of the receptor or ligands as well as downstream pathway activation. Our results imply that therapies that target the NOTCH pathway may be more widely suitable for HNSCC treatment than appreciated currently.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Signal Transduction


Zheng H, Wang X, Ma Y, et al.
The TCR γδ repertoire and relative gene expression characteristics of T-ALL cases with biclonal malignant Vδ1 and Vδ2 T cells.
DNA Cell Biol. 2014; 33(1):49-56 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Despite significant improvement in our understanding of T-cell acute lymphoblastic leukemia (T-ALL) biology and pathogenesis, many questions remain unanswered. In previous studies, we found a T-ALL case with two malignant T-cell clones with Vδ1Dδ2Dδ3Jδ1 and Vδ2Dδ3Jδ2 rearrangements. In this study, we further characterized T-ALL cases with two malignant clones containing Vδ1Dδ3Jδ1 and Vδ2Dδ1Jδ1 rearrangements using fine-tiling array comparative genomic hybridization, ligation-mediated polymerase chain reaction (LM-PCR), sequencing, and reverse transcription polymerase chain reaction (RT-PCR) analysis. We further analyzed the distribution and clonality of the T-cell receptor (TCR) Vγ and Vδ subfamily T cells in the two T-ALL cases by RT-PCR and GeneScan. Monoclonal Vδ1 and Vδ2 subfamilies were confirmed in both samples, the Vδ3 through Vδ7 subfamilies could not be detected in the T-ALL samples, whereas the oligoclonal Vδ8 subfamily could be identified. Based on the clinical finding that both of the T-ALL cases with two malignant T-cell clones had a poor outcome, we attempted to compare the expression pattern of genes related to T-cell activation and proliferation between cases with the malignant Vδ1 and Vδ2 T-cell clones and T-ALL cases with a mono-malignant Vα T-cell clone. We selected two T-ALL cases with VαJα rearrangements and analyzed the expression level of Notch1, TAL1, and the CARMA-BCL10-MALT-A20-NF-κB pathway genes by real-time PCR. A20 had significantly higher expression in the biclonal compared with the monoclonal T-ALL group (p=0.0354), and there was a trend toward higher expression for the other genes in the biclonal group with the exception of TAL1, although the differences were not statistically significant. In conclusion, we identified two T-ALL cases with biclonal malignant T-cell clones and described the characteristics of the biclonal T-ALL subtype and its gene expression pattern. Thus, our findings may improve the understanding of biclonal T-ALL.


Suresh S, McCallum L, Crawford LJ, et al.
The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia.
J Pathol. 2013; 231(3):378-87 [PubMed] Related Publications
Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia (CML) is not well established. We previously reported BCR-ABL down-regulation of a novel haematopoietic regulator, CCN3, in CML; CCN3 is a non-canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML. In K562 cells, BCR-ABL silencing reduced full-length NOTCH1 (NOTCH1-FL) and inhibited the cleavage of NOTCH1 intracellular domain (NOTCH1-ICD), resulting in decreased expression of the NOTCH1 targets c-MYC and HES1. K562 cells stably overexpressing CCN3 (K562/CCN3) or treated with recombinant CCN3(rCCN3) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1-ICD, p < 0.05).Gamma secretase inhibitor (GSI), which blocks NOTCH1 signalling, reduced K562/CCN3 colony formation but increased that of K562/control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR-ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML.

Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology Signal Transduction Imatinib (Glivec)


Szuhai K, de Jong D, Leung WY, et al.
Transactivating mutation of the MYOD1 gene is a frequent event in adult spindle cell rhabdomyosarcoma.
J Pathol. 2014; 232(3):300-7 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and adolescents, being characterized by expression of genes and morphological and ultrastructural features of sarcomeric differentiation. The spindle cell variant of rhabdomyosarcoma (spindle cell RMS) in adults has been defined as an entity, separated from embryonal rhabdomyosarcoma (ERMS), with unfavourable clinical outcome. So far, no recurrent genetic alteration has been identified in the adult form of spindle cell RMS. We studied a case of adult spindle cell RMS using next-generation sequencing (NGS) after exome capture. Using this approach, we identified 31 tumour-specific somatic alterations and selected four genes with predicted functional relevance to muscle differentiation and growth. MYOD1, KIF18A, NOTCH1, and EML5 were further tested for mutations using Sanger sequencing on DNA from FFPE samples from 16 additional, adult spindle cell RMS samples. The highly conserved sequence homology of MYOD1 with other myogenic transcription factors prompted us to screen the basic DNA-binding domains of MYF5, MYF6 and MYOG for mutations. From the investigated 17 samples, seven (41%) showed homozygous mutation of MYOD1, indicating a critical role in this rare subtype of adult spindle cell RMS, while no mutations were found in any of the other genes involved in myogenic differentiation. The p.L122R mutation occurs in the conserved DNA binding domain in MYOD1 and leads to transactivation and MYC-like functions. MYOD1 homozygous mutations are frequent, recurrent and pathognomonic events in adult-type spindle cell RMS.

Related: Rhabdomyosarcoma Soft Tissue Sarcomas


Gallo Llorente L, Luther H, Schneppenheim R, et al.
Identification of novel NOTCH1 mutations: increasing our knowledge of the NOTCH signaling pathway.
Pediatr Blood Cancer. 2014; 61(5):788-96 [PubMed] Related Publications
BACKGROUND: Alterations in the NOTCH1 signaling pathway are found in about 60% of pediatric T-ALL, but its impact on prognosis remains unclear.
PROCEDURE: We extended the previously published CoALL cohort (n = 74) to a larger cohort (n = 127) and additionally included 38 Argentine patients from ALL IC-BFM to potentially identify novel mutations and decipher a stronger discriminatory effect on the genotype/phenotype relationship with regard to early treatment response and long-term outcome.
RESULTS: Overall, 101 out of 165 (61.2%) T-ALL samples revealed at least one NOTCH1 mutation, 28 of whom had combined NOTCH1 and FBXW7 mutations. Eight T-ALL samples (4.8%) exclusively revealed FBXW7 mutations. Fifty-six T-ALL (33.9%) exhibited a wild-type configuration of either gene. Four novel NOTCH1 mutations were identified localized in the C-terminal PEST domain, in the rarely affected LNR repeat domain and in the ankyrin domain. Novel LNR mutations may contribute to a better understanding of the structure of the NOTCH1 negative regulatory region (NRR) and the R1946 mutation in the ankyrin domain may represent an unusual loss-of-function mutation.
CONCLUSIONS: Overall, NOTCH1 pathway mutations did not affect the relapse rate and outcome of the extended T-ALL cohort uniformly treated according to CoALL protocols, although NOTCH1 mutations were associated with good response to induction therapy (P = 0.009). Individually, HD and PEST domain mutations might exert distinct functional effects on cellular homeostasis under treatment NOTCH1 pathway activity with prognostic implications.

Related: Signal Transduction FBXW7 gene


Court H, Amoyel M, Hackman M, et al.
Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression.
J Clin Invest. 2013; 123(11):4681-94 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
RAS is the most frequently mutated oncogene in human cancers. Despite decades of effort, anti-RAS therapies have remained elusive. Isoprenylcysteine carboxylmethyltransferase (ICMT) methylates RAS and other CaaX-containing proteins, but its potential as a target for cancer therapy has not been fully evaluated. We crossed a Pdx1-Cre;LSL-KrasG12D mouse, which is a model of pancreatic ductal adenocarcinoma (PDA), with a mouse harboring a floxed allele of Icmt. Surprisingly, we found that ICMT deficiency dramatically accelerated the development and progression of neoplasia. ICMT-deficient pancreatic ductal epithelial cells had a slight growth advantage and were resistant to premature senescence by a mechanism that involved suppression of cyclin-dependent kinase inhibitor 2A (p16INK4A) expression. ICMT deficiency precisely phenocopied Notch1 deficiency in the Pdx1-Cre;LSL-KrasG12D model by exacerbating pancreatic intraepithelial neoplasias, promoting facial papillomas, and derepressing Wnt signaling. Silencing ICMT in human osteosarcoma cells decreased Notch1 signaling in response to stimulation with cell-surface ligands. Additionally, targeted silencing of Ste14, the Drosophila homolog of Icmt, resulted in defects in wing development, consistent with Notch loss of function. Our data suggest that ICMT behaves like a tumor suppressor in PDA because it is required for Notch1 signaling.

Related: Cancer of the Pancreas Pancreatic Cancer Signal Transduction


Arruga F, Gizdic B, Serra S, et al.
Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia.
Leukemia. 2014; 28(5):1060-70 [PubMed] Related Publications
The purpose of this study was to compare the expression and function of NOTCH1 in chronic lymphocytic leukemia (CLL) patients harboring a wild-type (WT) or mutated NOTCH1 gene. NOTCH1 mRNA and surface protein expression levels were independent of the NOTCH1 gene mutational status, consistent with the requirement for NOTCH1 signaling in this leukemia. However, compared with NOTCH1-WT CLL, mutated cases displayed biochemical and transcriptional evidence of an intense activation of the NOTCH1 pathway. In vivo, expression and activation of NOTCH1 was highest in CLL cells from the lymph nodes as confirmed by immunohistochemistry. In vitro, the NOTCH1 pathway was rapidly downregulated, suggesting that signaling relies upon micro-environmental interactions even in NOTCH1-mutated cases. Accordingly, co-culture of Jagged1(+) (the NOTCH1 ligand) nurse-like cells with autologous CLL cells sustained NOTCH1 activity over time and mediated CLL survival and resistance against pro-apoptotic stimuli, both abrogated when NOTCH1 signaling was pharmacologically switched off. Together, these results show that NOTCH1 mutations have stabilizing effects on the NOTCH1 pathway in CLL. Furthermore, micro-environmental interactions appear critical in activating the NOTCH1 pathway both in WT and mutated patients. Finally, NOTCH1 signals may create conditions that favor drug resistance, thus making NOTCH1 a potential molecular target in CLL.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Signal Transduction


Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, et al.
Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study.
J Clin Oncol. 2013; 31(34):4333-42 [PubMed] Related Publications
PURPOSE: The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse.
PATIENTS AND METHODS: In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion).
RESULTS: N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001).
CONCLUSION: These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.

Related: PTEN KRAS gene NRAS gene FBXW7 gene


Beà S, Valdés-Mas R, Navarro A, et al.
Landscape of somatic mutations and clonal evolution in mantle cell lymphoma.
Proc Natl Acad Sci U S A. 2013; 110(45):18250-5 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.

Related: Mantle Cell Lymphoma NOTCH2 gene BCL1 Gene (CCND1)


Dey N, Young B, Abramovitz M, et al.
Differential activation of Wnt-β-catenin pathway in triple negative breast cancer increases MMP7 in a PTEN dependent manner.
PLoS One. 2013; 8(10):e77425 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Mutations of genes in tumor cells of Triple Negative subset of Breast Cancer (TNBC) deregulate pathways of signal transduction. The loss of tumor suppressor gene PTEN is the most common first event associated with basal-like subtype (Martins, De, Almendro, Gonen, and Park, 2012). Here we report for the first time that the functional upregulation of secreted-MMP7, a transcriptional target of Wnt-β-catenin signature pathway in TNBC is associated to the loss of PTEN. We identified differential expression of mRNAs in several key-components genes, and transcriptional target genes of the Wnt-β-catenin pathway (WP), including beta-catenin, FZD7, DVL1, MMP7, c-MYC, BIRC5, CD44, PPARD, c-MET, and NOTCH1 in FFPE tumors samples from TNBC patients of two independent cohorts. A similar differential upregulation of mRNA/protein for beta-catenin, the functional readout of WP, and for MMP7, a transcriptional target gene of beta-catenin was observed in TNBC cell line models. Genetic or pharmacological attenuation of beta-catenin by SiRNA or WP modulators (XAV939 and sulindac sulfide) and pharmacological mimicking of PTEN following LY294002 treatment downregulated MMP7 levels as well as enzymatic function of the secreted MMP7 in MMP7 positive PTEN-null TNBC cells. Patient data revealed that MMP7 mRNA was high in only a subpopulation of TNBC, and this subpopulation was characterized by a concurrent low expression of PTEN mRNA. In cell lines, a high expression of casein-zymograph-positive MMP7 was distinguished by an absence of functional PTEN. A similar inverse relationship between MMP7 and PTEN mRNA levels was observed in the PAM50 data set (a correlation coefficient of -0.54). The PAM50 subtype and outcome data revealed that the high MMP7 group had low pCR (25%) and High Rd (74%) in clinical stage T3 pathologic response in contrast to the high pCR (40%) and low residual disease (RD) (60%) of the low MMP7 group.

Related: PTEN Signal Transduction


Alqudah MA, Agarwal S, Al-Keilani MS, et al.
NOTCH3 is a prognostic factor that promotes glioma cell proliferation, migration and invasion via activation of CCND1 and EGFR.
PLoS One. 2013; 8(10):e77299 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Using a GWA analysis of a comprehensive glioma specimen population, we identified whole gain of chromosome 19 as one of the major chromosomal aberrations that correlates to patients' outcomes. Our analysis of significant loci revealed for the first time NOTCH3 as one of the most significant amplification. NOTCH3 amplification is associated with worse outcome compared to tumors with non-amplified locus. NOTCH receptors (NOTCH1-4) are key positive regulators of cell-cell interactions, angiogenesis, cell adhesion and stem cell niche development which have been shown to play critical roles in several human cancers. Our objective is to determine the molecular roles of NOTCH3 in glioma pathogenesis and aggressiveness. Here we show for the first time that NOTCH3 plays a major role in glioma cell proliferation, cell migration, invasion and apoptosis. Therefore, our study uncovers the prognostic value and the oncogenic function of NOTCH3 in gliomagenesis and supports NOTCH3 as a promising target of therapy in high grade glioma. Our studies allowed the identification of a subset of population that may benefit from GSI- or anti-NOTCH3- based therapies. This may lead to the design of novel strategies to improve therapeutic outcome of patients with glioma by establishing medical and scientific basis for personalized chemotherapies.

Related: Apoptosis NOTCH3


Clay MR, Varma S, West RB
MAST2 and NOTCH1 translocations in breast carcinoma and associated pre-invasive lesions.
Hum Pathol. 2013; 44(12):2837-44 [PubMed] Related Publications
There are several mutations and structural variations common to breast cancer. Many of these genomic changes are thought to represent driver mutations in oncogenesis. Less well understood is how and when these changes take place in breast cancer development. Previous studies have identified gene rearrangements in the microtubule-associated serine-threonine kinase (MAST) and NOTCH gene families in 5% to 7% of invasive breast cancers. Some of these translocations can be detected by fluorescence in situ hybridization (FISH) allowing for examination of the correlation between these genomic changes and concurrent morphologic changes in early breast neoplasia. NOTCH and MAST gene rearrangements were identified by FISH in a large series of breast cancer cases organized on tissue microarrays (TMA). When translocations were identified by TMA, we performed full cross-section FISH to evaluate concurrent pre-invasive lesions. FISH break-apart assays were designed for NOTCH1 and MAST2 gene rearrangements. Translocations were identified in 16 cases of invasive carcinoma; 10 with MAST2 translocations (2.0%) and 6 cases with NOTCH1 translocations (1.2%). Whole section FISH analysis of these cases demonstrated that the translocations are present in the majority of concurrent ductal carcinoma in situ (DCIS) (6/8). When DCIS wasn't associated with an invasive component, it was never translocated (0/170, P=.0048). We have confirmed the presence of MAST and NOTCH family gene rearrangements in invasive breast carcinoma, and show that FISH studies can effectively be used with TMAs to screen normal, pre-invasive, and coexisting invasive disease. Our findings suggest that these translocations occur during the transition to DCIS and/or invasive carcinoma.

Related: Breast Cancer FISH


Koch U, Radtke F
Notch in T-ALL: new players in a complex disease.
Trends Immunol. 2011; 32(9):434-42 [PubMed] Related Publications
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy of thymocytes affecting preferentially children and adolescents. The disease is heterogeneous and characterized by a large set of chromosomal and genetic alterations that deregulate the growth of maturing thymocytes. The identification of activating point mutations in NOTCH1 in more then 50% of all T-ALL cases highlights the NOTCH1 cascade as a central player of T-ALL pathogenesis. In this review, we summarize and update more recent findings on the molecular mechanisms of T-ALL with a particular emphasis on the oncogenic properties of aberrant NOTCH1 signaling.

Related: Signal Transduction


Agrawal N, Frederick MJ, Pickering CR, et al.
Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.
Science. 2011; 333(6046):1154-7 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology FBXW7 gene


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