Weng AP, Ferrando AA, Lee W, Morris 4th JP, Silverman LB, Sanchez-Irizarry C et al.. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306: 269-271

Harvard University, Cambridge, Massachusetts, United States
Science (Impact Factor: 33.61). 11/2004; 306(5694):269-71. DOI: 10.1126/science.1102160
Source: PubMed


Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of
human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular
heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated
NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with
NOTCH signaling.

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Available from: Andrew Weng, May 02, 2014
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    • "Having directly examined the mechanical unfolding and cleavage of the hN2-NRR in proof-of-feasibility of this proposed activation mechanism [18], we now increase insight into the mechanical properties of the NRR by combining experimental and computational unfolding studies with mutagenesis. Mutations were made to hN2-NRR at residue positions previously shown to cause a gain-of-phenotype in hN1 activation [6] [7]. The equivalent mutations in hN1 affect the stability of the NRR, specifically the HD domain, as demonstrated by more ready dissociation of S1-cleaved hN1-NRR variants into two subunits, HD-N and HD-C [28]. "
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    ABSTRACT: The Notch signalling pathway is fundamental to cell differentiation in developing and self-renewing tissues. Notch is activated upon ligand-induced conformational change of the Notch negative regulatory region (NRR), unmasking a key proteolytic site (S2) and facilitating downstream events. The favoured model requires endocytosis of a tightly bound ligand to transmit force to the NRR region, sufficient to cause a structural change that exposes the S2 site. We have previously shown, using atomic force microscopy and molecular dynamics simulations, that application of force to the N-terminus of the Notch2 NRR facilitates metalloprotease cleavage at an early stage in the unfolding process. Here, mutations are made within the heterodimerization (HD) domain of the NRR that are known to cause constitutive activation of Notch1 whilst having no effect on the chemical stability of Notch2. Comparison of the mechanical stability and simulated forced unfolding of recombinant Notch2 NRR proteins demonstrates a reduced stability following mutation and identifies two critical structural elements of the NRR in its response to force – the linker region between Lin12-Notch repeats LNRA and LNRB and the α3 helix within the HD domain – both of which mask the S2 cleavage site prior to Notch activation. In two mutated proteins, the LNRC:HD domain interaction is also reduced in stability. The observed changes to mechanical stability following these HD domain mutations highlight key regions of the Notch2 NRR that are important for mechanical, but not chemical, stability. This research could also help determine the fundamental differences in the NRRs of Notch1 and Notch2.
    Full-text · Article · Jul 2015 · FEBS Open Bio
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    • "Lymphocyte precursors acquire genetic and epigenetic alterations, resulting in a continuous signal of proliferation and a blockage on the differentiation, leading to the malignancy [1]. Although some modification in genome, like gene NOTCH1 [2], TEL-AML1 [3], Philadelphia chromosome [4], and exposure to carcinogenic factors, like aromatic hydrocarbons [5], ionizing radiation [6] and air pollution [7] have been described to influence the ALL pathogenesis, they explain a few percentage of the cases. Neoplastic cells are able to modulate the tumor microenvironment to its favor by producing cytokines, recruiting regulatory cells, like Tregs and Myeloid Derived Suppressor Cells (MDSC), which help the tumor escape immunological surveillance [8]. "
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    ABSTRACT: Acute Lymphoblastic Leukemia is the leading form of cancer in infancy, and compelling evidences suggest an involvement of altered immune competence on this malignancy pathogenesis. Interleukin 10 (IL-10) is a pleiotropic cytokine designated as an immunosuppressive molecule, but may act as an immunostimulant factor in cancer development and progression. An IL-10 single nucleotide polymorphism (SNP) rs1800896 has been associated with disease progression to ALL, and might influence cytokine expression. This study analyzed the IL-10 rs1800896 polymorphism and performed a case-control study to determine the significant associations with ALL susceptibility and prognosis. IL-10 plasma levels were determined and associated with genotypes and disease phase. The study consisted of 67 childhood ALL patients and 75 age-related healthy controls. The rs1800896 was not associated with ALL susceptibility or risk of relapse. No significant association was observed between different genotypes of the rs1800896 and plasma levels of IL-10. Cytokine plasma levels were significantly higher in the diagnosis group (9.71pg/mL±3.7), comparing to the treatment (3.48pg/mL±1.3; p=0.01) and remission phase (0.12pg/mL±0.1; p=0.0001) groups. This work indicates that the IL-10 plasma expression is altered from ALL disease diagnosis and remission. Moreover, prospective studies will establish the functional role of IL-10 in immune modulation in childhood ALL. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Blood Cells Molecules and Diseases
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    • "The role of NOTCH as a potential target for cancer therapy is a new field of research, as the initial observation of its importance in cancer was known only in 2004 (Weng et al. 2004). As discussed in this review, the significance of NOTCH in myeloid leukaemias is not well defined unlike its oncogenic potential in T-ALL. "
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    ABSTRACT: The NOTCH pathway is an evolutionarily conserved signalling network, which is fundamental in regulating developmental processes in invertebrates and vertebrates (Gazave et al. in BMC Evol Biol 9:249, 2009). It regulates self-renewal (Butler et al. in Cell Stem Cell 6:251-264, 2010), differentiation (Auderset et al. in Curr Top Microbiol Immunol 360:115-134, 2012), proliferation (VanDussen et al. in Development 139:488-497, 2012) and apoptosis (Cao et al. in APMIS 120:441-450, 2012) of diverse cell types at various stages of their development. NOTCH signalling governs cell-cell interactions and the outcome of such responses is highly context specific. This makes it impossible to generalize about NOTCH functions as it stimulates survival and differentiation of certain cell types, whereas inhibiting these processes in others (Meier-Stiegen et al. in PLoS One 5:e11481, 2010). NOTCH was first identified in 1914 in Drosophila and was named after the indentations (notches) present in the wings of the mutant flies (Bigas et al. in Int J Dev Biol 54:1175-1188, 2010). Homologs of NOTCH in vertebrates were initially identified in Xenopus (Coffman et al. in Science 249:1438-1441, 1990) and in humans NOTCH was first identified in T-Acute Lymphoblastic Leukaemia (T-ALL) (Ellisen et al. in Cell 66:649-61, 1991). NOTCH signalling is integral in neurogenesis (Mead and Yutzey in Dev Dyn 241:376-389, 2012), myogenesis (Schuster-Gossler et al. in Proc Natl Acad Sci U S A 104:537-542, 2007), haematopoiesis (Bigas et al. in Int J Dev Biol 54:1175-1188, 2010), oogenesis (Xu and Gridley in Genet Res Int 2012:648207, 2012), differentiation of intestinal cells (Okamoto et al. in Am J Physiol Gastrointest Liver Physiol 296:G23-35, 2009) and pancreatic cells (Apelqvist et al. in Nature 400:877-881, 1999). The current review will focus on NOTCH signalling in normal and malignant blood cell production or haematopoiesis.
    Full-text · Article · Feb 2015 · Journal of Cell Communication and Signaling
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