Ninette Amariglio

Sheba Medical Center, Gan, Tel Aviv, Israel

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Publications (283)1526.23 Total impact

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    British Journal of Haematology 03/2015; DOI:10.1111/bjh.13345 · 4.96 Impact Factor
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    ABSTRACT: Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an N(6)-methyladenosine (m(6)A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout pre-implantation epiblasts and naïve embryonic stem cells (ESCs) are depleted for m(6)A in mRNAs and yet, are viable. However, they fail to adequately terminate their naïve state, and subsequently undergo aberrant and restricted lineage priming at the post-implantation stage, leading to early embryonic lethality. m(6)A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo, and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner. Copyright © 2015, American Association for the Advancement of Science.
    Science 02/2015; 347(6225):1002-1006. DOI:10.1126/science.1261417 · 31.48 Impact Factor
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    ABSTRACT: Insights into the ontogeny of the human fetal adaptive immune system are of great value for understanding immunocompetence of the developing fetus. However, to date, this has remained largely uncharted territory, in large part because blood samples from healthy, early gestation fetuses have been hard to come by. In a comprehensive study, we analyzed levels of T cell receptor excision circles (TRECs), signal-joint κ receptor excision circles (sjKRECs), and intron recombination signal sequence-K-deleting element (iRSS-Kde) rearrangement, and T and B lymphocyte repertoire clonality in human fetuses from 12 to 26 weeks of gestational age. Using next-generation sequencing, we analyzed the diversity and complexity of T cell receptor β (TRB) and immunoglobulin heavy chain (IGH) repertoires in four fetuses at 12, 13, 22, and 26 weeks of gestation and in healthy full-term infants. We report the progressive increase of TREC, sjKREC, and iRSS-Kde levels over time and confirm that B cell development precedes T cell development in the human fetus. Temporally and spatially regulated maturation of B and T cell repertoire diversity and complexity during human fetal development was observed, including evidence that immunoglobulin somatic hypermutation and class switch recombination occur already during intrauterine life. Our results help define physiological levels of immunodeficiency in premature infants and may serve as a reference for future studies aimed at investigating the impact of intrauterine pathologies on fetal immune development and function. Copyright © 2015, American Association for the Advancement of Science.
    Science translational medicine 02/2015; 7(276):276ra25. DOI:10.1126/scitranslmed.aaa0072 · 14.41 Impact Factor
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    ABSTRACT: A-to-I RNA editing has been recently shown to be a widespread phenomenon with millions of sites spread in the human transcriptome. However, only few are known to be located in coding sequences and modify the amino acid sequence of the protein product. Here, we used high-throughput data, variant prediction tools and protein structural information in order to find structural and functional preferences for coding RNA editing. We show that RNA editing has a unique pattern of amino-acid changes characterized by enriched stop-to-tryptophan changes, positive-to-neutral and neutral-to-positive charge changes. RNA editing tends to have stronger structural effect than equivalent A-to-G SNPs but weaker effect than random A-to-G mutagenesis events. Sites edited at low level tend to be located at conserved positions with stronger predicted deleterious effect on proteins comparing to sites edited at high frequencies. Lowly edited sites tend to destabilize the protein structure and affect amino acids with larger number of intra-molecular contacts. Still, some highly edited sites are predicted also to prominently affect structure and tend to be located at critical positions of the protein matrix and are likely to be functionally important. Using our pipeline, we identify and discuss several novel putative functional coding changing editing sites in the genes COPA (I164V), GIPC1 (T62A), ZN358 (K382R) and CCNI (R75G). © Proteins 2014;. © 2014 Wiley Periodicals, Inc.
    Proteins Structure Function and Bioinformatics 11/2014; 82(11). DOI:10.1002/prot.24672 · 2.92 Impact Factor
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    ABSTRACT: Ataxia telangiectasia (AT) is a rare genetic, multi-system disorder characterized by neurodegeneration, chromosome instability, B and T cell immunodeficiency and a predisposition to cancer. We examined immunologic parameters reflecting cell development and proliferation and their relevancy to the clinical phenotype in affected individuals. AT patients from the AT National Clinic in Israel underwent immunological investigation. Their T and B cell workup included lymphocyte subset counts, immunoglobulin levels, responses to mitogenic stimulations, TCR-Vβ families and BCR immunoglobulin heavy chain spectratyping, TCR rearrangement excision circles (TRECs) and Kappa-deleting recombination excision circles (KRECs). Thirty-seven AT patients (median age 12.7 years, range 4.2-25.1) were evaluated. CD20 B and CD3 T lymphocytes were decreased in 67 % and 64 % of the patients, respectively, while only 33 % of the patients had reduced lymphoproliferative responses. Almost all AT patients displayed extremely low TRECs and KRECs levels, irrespective of their age. Those levels were correlated to one another and to the amounts of CD3+ and CD20+ cells, respectively. Abnormal TCR-Vβ repertoires were found with different degrees of clonality or reduced expression in these AT patients. There was no clear clustering of expansions to specific TCR-Vβ genes. PCR spectratyping analysis of the FR2 IgH BCR gene rearrangements in peripheral blood was abnormal in 50 % of the patients. The immunodeficiency associated with AT is combined, remains low over time and not progressive. It is characterized by low TREC and KREC copies suggestive of abnormal T and B cell neogenesis.
    Journal of Clinical Immunology 05/2014; DOI:10.1007/s10875-014-0044-1 · 2.65 Impact Factor
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    ABSTRACT: Related to testes-specific, vespid and pathogenesis protein-1 (RTVP-1), also known as glioma pathogenesis-related protein 1, is highly expressed and has oncogenic features in glioblastoma (GBM; World Health Organization class IV). Promoter methylation has been found to control RTVP-1 expression in prostate carcinoma, Wilms' tumor, acute myeloid leukemia and melanoma. In this bi-institutional study, the methylation status of RTVP-1 in astrocytic brain malignancies (GBM and oligodendroglioma) was examined. The RTVP-1 promoter was hypomethylated in GBM compared with non-tumor brain samples, but was hypermethylated in oligodendroglioma. RTVP-1 methylation correlated with RTVP-1 expression at the mRNA level. In GBM, hypermethylation of the RTVP-1 promoter was associated with improved overall survival although with no statistical significance.
    Oncology letters 04/2014; 7(4):1209-1212. DOI:10.3892/ol.2014.1829 · 0.99 Impact Factor
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    ABSTRACT: Adenosine to inosine (A-to-I) RNA editing is a base recoding process within precursor messenger RNA, catalyzed by members of the adenosine deaminase acting on RNA (ADAR) family. A notable example occurs at the Q/R site of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor subunit GluA2. Abnormally, low editing at this site leads to excessive calcium influx and cell death. We studied hippocampus and caudate samples from Alzheimer's disease (AD) patients and age-matched healthy controls, using direct sequencing and a high accuracy primer-extension technique to assess RNA editing at the Q/R GluA2 site. Both techniques revealed lower, more variable RNA editing in AD, specific to the hippocampus and the GluA2 site. Deficient editing also characterized the hippocampus of apolipoprotein ε4 allele carriers, regardless of clinical diagnosis. In AD, messenger RNA expression of neuronal markers was decreased in the hippocampus, and expression of the Q/R-site editing enzyme ADAR2 was decreased in caudate. These findings provide a link between neurodegenerative processes and deficient RNA editing of the GluA2 Q/R site, and may contribute to both diagnosis and treatment of AD.
    Neurobiology of aging 03/2014; 35(8). DOI:10.1016/j.neurobiolaging.2014.02.018 · 4.85 Impact Factor
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    ABSTRACT: Polyploidy has been recognized for many years as an important hallmark of cancer cells. Polyploid cells can arise through cell fusion, endoreplication and abortive cell cycle. The inner nuclear membrane protein LAP2beta plays key roles in nuclear envelope breakdown and reassembly during mitosis, initiation of replication and transcriptional repression. Here we studied the function of LAP2beta in the maintenance of cell ploidy state, a role which has not yet been assigned to this protein. By knocking down the expression of LAP2beta, using both viral and non-viral RNAi approaches in osteosarcoma derived U2OS cells, we detected enlarged nuclear size, nearly doubling of DNA content and chromosomal duplications, as analyzed by fluorescent in situ hybridization and spectral karyotyping methodologies. Spectral karyotyping analyses revealed that near-hexaploid karyotypes of LAP2beta knocked down cells consisted of not only seven duplicated chromosomal markers, as could be anticipated by genome duplication mechanism, but also of four single chromosomal markers. Furthermore, spectral karyotyping analysis revealed that both of two near-triploid U2OS sub-clones contained the seven markers that were duplicated in LAP2beta knocked down cells, whereas the four single chromosomal markers were detected only in one of them. Gene expression profiling of LAP2beta knocked down cells revealed that up to a third of the genes exhibiting significant changes in their expression are involved in cancer progression. Our results suggest that nuclear fusion mechanism underlies the polyploidization induction upon LAP2beta reduced expression. Our study implies on a novel role of LAP2beta in the maintenance of cell ploidy status. LAP2beta depleted U2OS cells can serve as a model to investigate polyploidy and aneuploidy formation by nuclear fusion mechanism and its involvement in cancerogenesis.
    Molecular Cytogenetics 01/2014; 7(1):9. DOI:10.1186/1755-8166-7-9 · 2.66 Impact Factor
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    ABSTRACT: It is commonly accepted that the presence of high amounts of maternal T cells excludes Omenn syndrome (OS) in severe combined immunodeficiency (SCID). We report a SCID patient with a novel mutation in the RAG1 gene (4-BP DEL.1406 TTGC) who presented with immunodeficiency and OS. Several assays, including representatives of specific T cell receptors (TCR), Vβ families and TCR-γ rearrangements, were performed in order to better understand the nature and origin of the patient's T cells. The patient had oligoclonal T cells which, based on the patient-mother HLA-B50 mismatch, were either autologous or of maternal origin. These cell populations were different in their numbers of regulatory T cell (Treg) and the diversity of TCR repertoires. This is the first description of the coexistence of large amounts of clonal expanded autologous and transplacental-acquired maternal T cells in RAG1-deficient SCID.
    Clinical & Experimental Immunology 01/2014; 176(3). DOI:10.1111/cei.12273 · 3.28 Impact Factor
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    ABSTRACT: one third of CML patients treated with first line imatinib have suboptimal responses or treatment failures with increased risk for disease progression. Imatinib is actively transported into cells by the SLC22A1 transporter (hOCT1)and its genetic variants may affect intracellular drug import. We studied the effect of SLC22A1 genetic variants on long term outcomes of imatinib treated patients. a total of 167 patients, 94% in chronic phase, were analyzed for rs41267797, rs683369, rs12208357 and rs628031 variants using the SequenomMassARRAY platform. rates of CHR, MCyR, CCyR and MMolR were not significantly different according to allelic variants. However, patients with AA or GA rs628031 genotypes had a higher incidence of poor response to imatinib compared to the GG genotype (47% compared to 29%, p=0.06), and a higher rate of KD mutation discovery (8/16 vs. 5/27, p=0.04), suggesting that secondary resistance was more common in these genotypes. Median EFS was shorter for rs628031 genotype AA/AG compared with the GG genotype (61 months and not reached, respectively, p=0.05), and 5 years OS rates were lower for patients with the rs628031 genotypes AA/AG compared with the GG genotype (88% and 97%, respectively, p=0.03). Patients with AA/GA rs628031 and additional rare genotypes had worse EFS and OS compared to patients with only AA/GA rs628031 (p=0.02 for EFS and 0.01 for OS). There was no difference in pretreatment SLC22A1 mRNA expression levels in patients with rs628031 genotypes GG/AA or GA. studying SLC22A1 genetic variants prior to TKI initiation could influence treatment decisions. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 11/2013; 92(4). DOI:10.1111/ejh.12235 · 2.41 Impact Factor
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    ABSTRACT: F11R is a cell adhesion molecule found on the surface of human platelets. It plays a role in platelet aggregation, cell migration and cell proliferation. F11R is subjected to RNA editing, a post-transcriptional modification which affects RNA structure, stability, localization, translation and splicing. RNA editing in the 3'UTR of F11R and RNA levels are increased upon hypoxia. We therefore set to examine if RNA editing plays a role in the increase of F11R RNA seen upon hypoxic conditions. We show that ADAR1, but not ADAR2, takes part in the editing of F11R however editing alone is not sufficient for obtaining an elevation in RNA levels. In addition we show that hyper-edited mature mRNAs are retained in the nucleus and are associated with p54(nrb). We therefore conclude that hypoxia-induced edited RNAs of F11R are preferentially stabilized and accumulate in the nucleus preventing their export to the cytoplasm for translation. This mechanism may be used by additional proteins in the cell as part of the cell's effort to reduce metabolism upon hypoxic stress.
    PLoS ONE 10/2013; 8(10):e77702. DOI:10.1371/journal.pone.0077702 · 3.53 Impact Factor
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    ABSTRACT: Enumeration of T cell receptor excision circles (TREC) was recently adopted as a neonatal screening assay for severe combined immunodeficiency (SCID). Enumeration of kappa-deleting recombination excision circle (KREC) copy numbers can be similarly used for early assessment of B cell lymphopenia. To assess the ability of TREC and KREC counts to identify patients with combined T and B cell immunodeficiency in a pilot study in Israel. We studied seven children born in Israel during the years 2010-2011 and later diagnosed with SCID, and an additional patient with pure B cell immunodeficiency. TREC and KREC in peripheral blood upon diagnosis and in their neonatal Guthrie cards were analyzed using real-time quantitative polymerase chain reaction, as were Guthrie cards with dried blood spots from healthy newborns and from normal and SCID-like controls. The first features suggestive of SCID presented at age 3.1 +/- 2.4 months in all patients. Yet, the diagnosis was made 4.1 +/- 2.9 months later. Their TREC were undetectable or significantly low at their clinical diagnosis and in their originally stored Guthrie cards, irrespective of the amount of their circulating T cells. KREC were undetectable in six SCID patients who displayed B cell lymphopenia in addition to T cell lymphopenia. KREC were also undetectable in one patient with pure B cell immunodeficiency. TREC and KREC quantification are useful screening tests for severe T and B cell immunodeficiency. Implementation of these tests is highly important especially in countries such as Israel where a high frequency of consanguinity is known to exist.
    The Israel Medical Association journal: IMAJ 08/2013; 15(8):404-9. · 0.90 Impact Factor
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    ABSTRACT: Dehydroepiandrosterone (DHEA), the main brain neurosteroid, has been implicated in various psychiatric disorders especially those including gender differences. We studied genetic variability in the DHEA-producing enzyme CYP17A1 in relation to anorexia nervosa (AN) susceptibility and AN-related co-morbidities. We performed analysis of 100 Israeli AN family trios accounting for CYP17A1 haplotypes characteristic of populations of European origin and studied genotype-phenotype relationships using correlation analyses and transmission disequilibrium test. Although our analysis revealed no evidence of association between CYP17A1 and AN per se, it revealed an association between specific CYP17A1 haplotypes and AN co-morbidity, specifically anxiety. We found that a common CYP17A1 haplotype (H1) was associated with higher anxiety in AN patients (Clinical Global Impression; CGI-anxiety ≥4). Moreover, H1 homozygotes were at higher risk for expressing high CGI-anxiety levels (OR = 3.7), and H1 was preferentially transmitted to AN patients with high CGI-anxiety levels (P = 0. 037). We suggest that CYP17A1 H1 haplotype may contribute to genetic predisposition to higher CGI-anxiety levels in AN patients and that this predisposition may be mediated by reduced CYP17A1 enzymatic activity and corresponding lower DHEA production.
    Archives of Women s Mental Health 06/2013; 16(5). DOI:10.1007/s00737-013-0363-x · 1.96 Impact Factor
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    ABSTRACT: Background Neutrophils are the predominant phagocytes that provide protection against bacterial and fungal infections. Genetically determined neutrophil disorders confer a predisposition to severe infections and reveal novel mechanisms that control vesicular trafficking, hematopoiesis, and innate immunity. Methods We clinically evaluated seven children from five families who had neutropenia, neutrophil dysfunction, bone marrow fibrosis, and nephromegaly. To identify the causative gene, we performed homozygosity mapping using single-nucleotide polymorphism arrays, whole-exome sequencing, immunoblotting, immunofluorescence, electron microscopy, a real-time quantitative polymerase-chain-reaction assay, immunohistochemistry, flow cytometry, fibroblast motility assays, measurements of apoptosis, and zebrafish models. Correction experiments were performed by transfecting mutant fibroblasts with the nonmutated gene. Results All seven affected children had homozygous mutations (Thr224Asn or Glu238Lys, depending on the child's ethnic origin) in VPS45, which encodes a protein that regulates membrane trafficking through the endosomal system. The level of VPS45 protein was reduced, as were the VPS45 binding partners rabenosyn-5 and syntaxin-16. The level of β1 integrin was reduced on the surface of VPS45-deficient neutrophils and fibroblasts. VPS45-deficient fibroblasts were characterized by impaired motility and increased apoptosis. A zebrafish model of vps45 deficiency showed a marked paucity of myeloperoxidase-positive cells (i.e., neutrophils). Transfection of patient cells with nonmutated VPS45 corrected the migration defect and decreased apoptosis. Conclusions Defective endosomal intracellular protein trafficking due to biallelic mutations in VPS45 underlies a new immunodeficiency syndrome involving impaired neutrophil function. (Funded by the National Human Genome Research Institute and others.).
    New England Journal of Medicine 06/2013; 369(1). DOI:10.1056/NEJMoa1301296 · 54.42 Impact Factor
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    ABSTRACT: Biopsy specimens from 23 early stage and 19 tumor-stage mycosis fungoides (MF) patients were evaluated for miR-155 expression by real-time qualitative PCR and compared with 15 biopsy specimens from patients with T-cell-rich inflammatory skin diseases. Significant upregulation of miR-155 was found in MF tumors compared with both early-stage MF lesions and controls. There was no difference in miR-155 expression between early-stage and inflammatory dermatoses. Using laser capture microdissection, it was found that miR-155 was significantly higher in the lymphoma cells in tumor stage compared with the intraepidermal lymphocytes in early stage. In contrast, there was no difference in miR-155 expression between the intraepidermal lymphocytes and the dermal lymphocytes in early-stage MF. These findings suggest that although miR-155 expression cannot serve to discriminate early-stage MF from inflammatory dermatoses; however, it is involved in the switch from the indolent early stage into the aggressive tumor stage of the disease.
    Experimental Dermatology 06/2013; 22(6):431-433. DOI:10.1111/exd.12161 · 4.12 Impact Factor

Publication Stats

8k Citations
1,526.23 Total Impact Points


  • 1995–2015
    • Sheba Medical Center
      • Cancer Research Center
      Gan, Tel Aviv, Israel
  • 1991–2014
    • Tel Aviv University
      • • Sackler Faculty of Medicine
      • • Faculty of Medicine
      • • Department of Pediatrics
      Tell Afif, Tel Aviv, Israel
  • 2013
    • Bar Ilan University
      Gan, Tel Aviv, Israel
  • 2012
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel
  • 2007
    • Meir Medical Center
      Kafr Saba, Central District, Israel
    • Technion - Israel Institute of Technology
      • Faculty of Biology
      Haifa, Haifa District, Israel
    • Ministry of Health (Israel)
      Yerushalayim, Jerusalem District, Israel
    • Baylor College of Medicine
      Houston, Texas, United States
  • 2002–2007
    • Weizmann Institute of Science
      • Department of Biological Regulation
  • 2006
    • Columbia University
      New York, New York, United States
  • 2005
    • University of Haifa
      • Institute of Evolution
      Haifa, Haifa District, Israel
  • 2004
    • Ben-Gurion University of the Negev
      Be'er Sheva`, Southern District, Israel
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2003
    • Charles University in Prague
      Praha, Praha, Czech Republic