NOTCH1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature reviews. Cancer (Impact Factor: 37.4). 06/2006; 6(5):347-59. DOI: 10.1038/nrc1880
Source: PubMed


The chromosomal translocation t(7;9) in human T-cell acute lymphoblastic leukaemia (T-ALL) results in deregulated expression of a truncated, activated form of Notch 1 (TAN1) under the control of the T-cell receptor-beta (TCRB) locus. Although TAN1 efficiently induces T-ALL in mouse models, t(7;9) is present in less than 1% of human T-ALL cases. The recent discovery of novel activating mutations in NOTCH1 in more than 50% of human T-ALL samples has made it clear that Notch 1 is far more important in human T-ALL pathogenesis than previously suspected.

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Available from: Harald von Boehmer, Nov 12, 2014
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    • "In the Notch-1 pathway, ligand binding results in the release of the Notch-1 intracellular domain (ICD), which translocates into the cell nucleus and interacts with DNA-binding protein CSL (CBF1/RBP-J, Su(H), Lag-1) to regulate expression of downstream genes [6] [7]. Notch-1 receptor–ligand interactions between bone marrow stromal cells (BMSCs) and HSCs may influence the self-renewal of HSCs and keep the cells at a preliminary stage [8]. Hughes et al. reported that osteosarcoma cell lines with the ability to metastasis have higher expression levels of Notch-1 [9]. "
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    ABSTRACT: Extra-medullary infiltration is still one of the main causes of recurrence and treatment failure of T-cell acute lymphoblastic leukemia (T-ALL). Intensive studies revealed that Notch pathway plays an important role in the invasion of tumor cells. Notch pathway can be triggered by binding of Notch receptors on T-ALL cells to their ligands on bone marrow stromal cells (BMSCs), which contributes to the development of T-ALL. However, the effect and molecular mechanisms of BMSCs in invasion of T-ALL cells remain unclear. To explore the effect of Notch-1 on the invasiveness of T-ALL cells, we co-cultured T-ALL cells with BMSCs (from healthy donors)/BMSCs* (from newly diagnosed T-ALL patients). The results demonstrated that BMSCs/BMSCs* promoted invasion of T-ALL cells through activating Notch-1 signalling. In particular, T-ALL cells showed a higher invasive potential in the presence of BMSCs* than BMSCs. Knockdown of Notch-1 prevented the positive effect of stromal cells-mediated invasion. Our study also showed that BMSCs/BMSCs*-induced Notch-1 activation increased the expression of matrix metalloprote inase-2 (MMP-2) and matrix metalloprote inase-9 (MMP-9), which increased invasiveness. These results provided theoretical and laboratory basis for the prevention and treatment of extra-medullary infiltration of T-ALL cells.
    Experimental Cell Research 01/2015; 332(1). DOI:10.1016/j.yexcr.2015.01.008 · 3.25 Impact Factor
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    • "NOTCH1 is crucial in T-cell differentiation and proliferation. NOTCH1 mutations appear in approximately 50% of acute T-lymphoblastic leukemia cases35. It has been reported that the significantly high expression level of NOTCH1 is positively correlated with acute T-lymphocyte leukemia (ATLL)36. "
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    ABSTRACT: Long-term exposure to benzene causes several adverse health effects, including an increased risk of acute myeloid leukemia. This study was to identify genetic alternations involved in pathogenesis of leukemia in benzene-exposed workers without clinical symptoms of leukemia. This study included 33 shoe-factory workers exposed to benzene at levels from 1 ppm to 10 ppm. These workers were divided into 3 groups based on the benzene exposure time, 1- < 7, 7- < 12, and 12- < 24 years. 17 individuals without benzene exposure history were recruited as controls. Cytogenetic analysis using Affymetrix Cytogenetics Array found copy-number variations (CNVs) in several chromosomes of benzene-exposed workers. Expression of targeted genes in these altered chromosomes, NOTCH1 and BSG, which play roles in leukemia pathogenesis, was further examined using real-time PCR. The NOTCH1 mRNA level was significantly increased in all 3 groups of workers, and the NOTCH1 mRNA level in the 12- < 24 years group was significantly higher than that in 1- < 7 and 7- < 12 years groups. Compared to the controls, the BSG mRNA level was significantly increased in 7- < 12 and 12- < 24 years groups, but not in the 1- < 7 years group. These results suggest that CNVs and leukemia-related gene expression might play roles in leukemia development in benzene-exposed workers.
    Scientific Reports 07/2014; 4:5369. DOI:10.1038/srep05369 · 5.58 Impact Factor
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    • "When the Notch receptor is triggered upon interaction with its ligands on neighboring cells, the Notch intracellular domain (NIC) is released from the membrane after proteolytic cleavages executed by γ-secretase-containing protease complexes. The NIC enters the nucleus and associates with the DNA-binding transcription factor RBP-J through its N-terminal RAM (RBP-J association molecule) domain, which transactivates promoters harboring RBP-J-binding sites by dissociating co-repressors, such as SMRT/N-CoR, HDAC, and MINT [1,8], and recruiting co-activators including Mastermind-like (MAML) and p300/CBP [9]. In T-ALL, activated Notch1 regulates cell proliferation and apoptosis by modulating the level and activities of the related molecules/pathways such as Hes1, c-Myc, PI3K/AKT, and NF-κB through canonical (RBP-J-dependent) and/or non-canonical (RBP-J-independent) signals [10,11]. "
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    ABSTRACT: Background Aberrantly activated Notch signaling has been found in more than 50% of patients with T-cell acute lymphoblastic leukemia (T-ALL). Current strategies that employ γ-secretase inhibitors (GSIs) to target Notch activation have not been successful. Many limitations, such as non-Notch specificity, dose-limiting gastrointestinal toxicity and GSI resistance, have prompted an urgent need for more effective Notch signaling inhibitors for T-ALL treatment. Human four-and-a-half LIM domain protein 1C (FHL1C) (KyoT2 in mice) has been demonstrated to suppress Notch activation in vitro, suggesting that FHL1C may be new candidate target in T-ALL therapy. However, the role of FHL1C in T-ALL cells remained unclear. Methods Using RT-PCR, we amplified full-length human FHL1C, and constructed full-length and various truncated forms of FHL1C. Using cell transfection, flow cytometry, transmission electron microscope, real-time RT-PCR, and Western blotting, we found that overexpression of FHL1C induced apoptosis of Jurkat cells. By using a reporter assay and Annexin-V staining, the minimal functional sequence of FHL1C inhibiting RBP-J-mediated Notch transactivation and inducing cell apoptosis was identified. Using real-time PCR and Western blotting, we explored the possible molecular mechanism of FHL1C-induced apoptosis. All data were statistically analyzed with the SPSS version 12.0 software. Results In Jurkat cells derived from a Notch1-associated T-ALL cell line insensitive to GSI treatment, we observed that overexpression of FHL1C, which is down-regulated in T-ALL patients, strongly induced apoptosis. Furthermore, we verified that FHL1C-induced apoptosis depended on the RBP-J-binding motif at the C-terminus of FHL1C. Using various truncated forms of FHL1C, we found that the RBP-J-binding motif of FHL1C had almost the same effect as full-length FHL1C on the induction of apoptosis, suggesting that the minimal functional sequence in the RBP-J-binding motif of FHL1C might be a new drug candidate for T-ALL treatment. We also explored the molecular mechanism of FHL1C overexpression-induced apoptosis, which suppressed downstream target genes such as Hes1 and c-Myc and key signaling pathways such as PI3K/AKT and NF-κB of Notch signaling involved in T-ALL progression. Conclusions Our study has revealed that FHL1C overexpression induces Jurkat cell apoptosis. This finding may provide new insights in designing new Notch inhibitors based on FHL1C to treat T-ALL.
    BMC Cancer 06/2014; 14(1):463. DOI:10.1186/1471-2407-14-463 · 3.36 Impact Factor
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