Genomes and Genes
b lymphocyte gene rearrangement
Summary: Ordered rearrangement of B-lymphocyte variable gene regions coding for the immunoglobulin chains, thereby contributing to antibody diversity. It occurs during the differentiation of the immature B-lymphocyte.
Publications176 found, 100 shown here
- B cell development pathwaysR R Hardy
Institute for Cancer Research, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, Pennsylvania 19111, USA
Annu Rev Immunol 19:595-621. 2001....
- AID and mismatch repair in antibody diversificationAlberto Martin
Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Chanin 403, Bronx, New York 10461, USA
Nat Rev Immunol 2:605-14. 2002
- Somatic hyperconversion diversifies the single Vh gene of the chicken with a high incidence in the D regionC A Reynaud
Basel Institute for Immunology, Switzerland
Cell 59:171-83. 1989..Allelic exclusion appears to be performed by restriction of a complete VDJ rearrangement to a single allele...
- IMGT/LIGM-DB, the IMGT comprehensive database of immunoglobulin and T cell receptor nucleotide sequencesVeronique Giudicelli
IMGT, the international ImMunoGeneTics information system, Laboratoire d Immunogenetique moleculaire, LIGM, Universite Montpellier II, Institut de Genetique Humaine IGH, UPR CNRS 1142, 141 rue de la Cardonille, 34396 Montpellier Cedex 5, France
Nucleic Acids Res 34:D781-4. 2006..They represent the main source of IG and TR gene and allele knowledge stored in IMGT/GENE-DB and in the IMGT reference directory. IMGT/LIGM-DB is freely available at http://imgt.cines.fr...
- IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysisXavier Brochet
IMGT, the international ImMunoGeneTics information system, Laboratoire d ImmunoGenetique Moleculaire LIGM, Universite Montpellier 2, Institut de Genetique Humaine IGH, UPR CNRS 1142, 141 rue de la Cardonille, 34396 Montpellier Cedex 5, France
Nucleic Acids Res 36:W503-8. 2008..The 'Advanced parameters' allow to modify default parameters used by IMGT/V-QUEST and IMGT/JunctionAnalysis according to the users' interest. IMGT/V-QUEST is freely available for academic research at http://imgt.cines.fr...
- The role of the non-homologous end-joining pathway in lymphocyte developmentSean Rooney
Howard Hughes Medical Institute, The Children s Hospital, The Department of Genetics, Harvard Medical School and The Center for Blood Research, Boston, MA 02115, USA
Immunol Rev 200:115-31. 2004..In this review, we discuss the factors that constitute this pathway as well as the evidence of their involvement in two lymphoid-specific DNA recombination events...
- Rapid generation of specific antibodies by enhanced homologous recombinationHidetaka Seo
Genetic Dynamics Research Unit, RIKEN Discovery Research Institute, 2 1 Hirosawa, Wako, Saitama 351 0198, Japan
Nat Biotechnol 23:731-5. 2005....
- Failure of B-cell differentiation in mice lacking the transcription factor EBFH Lin
Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California, San Francisco 94143, USA
Nature 376:263-7. 1995....
- Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient miceE Spanopoulou
Rockefeller University, New York, New York
Genes Dev 8:1030-42. 1994..These data also support the hypothesis that Rag-1 directly participates in the V(D)J recombination process...
- Helix-loop-helix proteins and lymphocyte developmentCornelis Murre
Division of Biological Sciences, University of California, San Diego, La Jolla, California 92903, USA
Nat Immunol 6:1079-86. 2005..This review discusses HLH proteins in lymphocyte development and homeostasis...
- Computational tools for understanding sequence variability in recombination signalsLindsay G Cowell
Department of Biostatistics and Bioinformatics, Center for Bioinformatics and Computational Biology, Duke University, Durham, NC, USA
Immunol Rev 200:57-69. 2004..These models successfully predict RS activity and identify functional, cryptic RSs (cRSs). These models permit studies to identify RSs and cRSs for empiric study and constitute a tool useful for understanding RS structure and function...
- Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoireSandra Weller
Institut National de Santé et de la Recherche Médicale U373, Paris, France
Blood 104:3647-54. 2004..It is therefore proposed that these IgM(+)IgD(+)CD27(+) B cells provide the splenic marginal zone with a diversified and protective preimmune repertoire in charge of the responses against encapsulated bacteria...
- V(D)J recombinationDavid G Schatz
Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 8011, USA
Immunol Rev 200:5-11. 2004
- Changes in histone acetylation are associated with differences in accessibility of V(H) gene segments to V-DJ recombination during B-cell ontogeny and developmentKristen Johnson
Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA
Mol Cell Biol 23:2438-50. 2003..Thus, changes in histone acetylation appear to be important for both promotion and inhibition of V-DJ rearrangement during B-cell ontogeny and development...
- Mechanism and control of class-switch recombinationJohn P Manis
Children s Hospital, Center for Blood Research and Dept of Genetics, Harvard Medical School, Boston, MA 02115, USA
Trends Immunol 23:31-9. 2002..In this review, we discuss the potential role of these factors in CSR, discuss potential relationships between CSR and somatic hypermutation, and speculate how CSR and related mechanisms might contribute to genomic instability...
- Lineage specification and plasticity in CD19- early B cell precursorsLynn L Rumfelt
Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
J Exp Med 203:675-87. 2006..A) stage, and B/T lymphoid plasticity persists until the CD19+ pro-B stage. Thus, MLP, CLP, and Fr. A represent progressively B lineage-specified stages in development, before the CD19+ B lineage-committed pro-B stage...
- Essential roles of the kappa light chain intronic enhancer and 3' enhancer in kappa rearrangement and demethylationMatthew Inlay
Section of Molecular Biology, Division of Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 0322, USA
Nat Immunol 3:463-8. 2002..Our findings also indicate that the two kappa enhancers play overlapping and distinct roles in the demethylation of kappa in B cells...
- Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switchingJing H Wang
Howard Hughes Medical Institute, Harvard Medical School, MA 02115, USA
J Exp Med 205:3079-90. 2008..Thus, Xrcc4/p53-deficient pro-B lymphomas routinely activate c-myc by gene amplification, whereas Xrcc4/p53-deficient peripheral B cell lymphomas routinely ectopically activate a single c-myc copy...
- Frequent aberrant immunoglobulin gene rearrangements in pro-B cells revealed by a bcl-xL transgeneW Fang
Department of Medicine, University of Minnesota Medical School, Minneapolis 55455, USA
Immunity 4:291-9. 1996..This analysis also demonstrated that immunoglobulin gene rearrangement is less precise than previously appreciated...
- Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in miceM J Mendez
Abgenix, Inc, Fremont, California 94555, USA
Nat Genet 15:146-56. 1997..Our results underscore the importance of the large Ig fragments with multiple V genes for restoration of a normal humoral immune response. These mice are likely to be a valuable tool for the generation of therapeutic antibodies...
- Mechanisms promoting translocations in editing and switching peripheral B cellsJing H Wang
Howard Hughes Medical Institute, USA
Nature 460:231-6. 2009..Our studies show peripheral B cells that attempt secondary V(D)J recombination, and determine a role for mechanistic factors in promoting recurrent translocations in tumours...
- Stepwise activation of the immunoglobulin mu heavy chain gene locusD Chowdhury
Rosenstiel Basic Medical Research Center and Department of Biology, Brandeis University, Waltham, MA 02454, USA
EMBO J 20:6394-403. 2001..We suggest that stepwise activation may be a general mechanism by which large segments of the genome are prepared for expression...
- Evidence of a critical architectural function for the RAG proteins in end processing, protection, and joining in V(D)J recombinationChia Lun Tsai
Department of Molecular Biophysics and Biochemistry, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA
Genes Dev 16:1934-49. 2002..Our results suggest that the RAG proteins have an architectural function in facilitating proper and efficient V(D)J joining, and a protective function in preventing degradation of broken ends prior to joining...
- Receptor selection in B and T lymphocytesD Nemazee
Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA
Annu Rev Immunol 18:19-51. 2000..New information about receptor editing in T cells and B-1 B cells is also discussed...
- Nonequivalent nuclear location of immunoglobulin alleles in B lymphocytesJ A Skok
Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
Nat Immunol 2:848-54. 2001..However, this differential recruitment and expression of Ig alleles was not typically seen among transformed B cell lines. These data raise the possibility that epigenetic factors help maintain the monoallelic expression of Ig...
- IMGT/V-QUEST, an integrated software program for immunoglobulin and T cell receptor V-J and V-D-J rearrangement analysisVeronique Giudicelli
IMGT, the international ImMunoGeneTics information system, Laboratoire d Immunogenetique moleculaire, LIGM, Institut de Genetique Humaine IGH, UPR CNRS 1142, 141 rue de la Cardonille, F 34396 Montpellier Cedex 5, France
Nucleic Acids Res 32:W435-40. 2004..IMGT/V-QUEST is currently available for human and mouse, and partly for non-human primates, sheep, chondrichthyes and teleostei. IMGT/V-QUEST is freely available at http://imgt.cines.fr...
- Continued RAG expression in late stages of B cell development and no apparent re-induction after immunizationW Yu
Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10021, USA
Nature 400:682-7. 1999..Our findings may help to reconcile a series of apparently contradictory observations, and suggest a new model for the mechanisms that regulate allelic exclusion, receptor editing and tolerance...
- Receptor editing in lymphocyte development and central toleranceDavid Nemazee
Department of Immunology, The Scripps Research Institute, Mail Drop IMM 29, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Nat Rev Immunol 6:728-40. 2006....
- RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombinationAdam G W Matthews
Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Nature 450:1106-10. 2007..Furthermore, our results provide the first evidence indicating that disrupting the read-out of histone modifications can cause an inherited human disease...
- Formation and resolution of double-strand break intermediates in V(D)J rearrangementD A Ramsden
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 0540, USA
Genes Dev 9:2409-20. 1995..Efficient formation of signal junctions may require cell cycle progression, or down-regulation of the recombination machinery...
- E47 is required for V(D)J recombinase activity in common lymphoid progenitorsLisa Borghesi
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
J Exp Med 202:1669-77. 2005..Taken together, this work defines a role for E47 in regulating lineage progression at the CLP stage in vivo and describes the first transcription factor required for lineage-specific recombinase activity...
- RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombinationM A Oettinger
Whitehead Institute for Biomedical Research, Cambridge, MA 02142
Science 248:1517-23. 1990..RAG-1 and RAG-2 might activate the expression of the V(D)J recombinase but, more likely, they directly participate in the recombination reaction...
- Hypermutation of immunoglobulin genes in memory B cells of DNA repair-deficient miceH Jacobs
Basel Institute for Immunology, CH 4005 Basel, Switzerland
J Exp Med 187:1735-43. 1998..This appears also to be true for mismatch repair, RAD54-dependent double-strand-break repair, and AAG-mediated base excision repair...
- Aberrant B cell development and immune response in mice with a compromised BCR complexR M Torres
Institute for Genetics, University of Cologne, Germany
Science 272:1804-8. 1996..B cells that do develop demonstrate a differential dependence on Ig-alpha signaling in antibody responses such that a signaling-competent Ig-alpha appears to be critical for the response to T-independent, but not T-dependent, antigens...
- Increased accumulation of hybrid V(D)J joins in cells expressing truncated versus full-length RAGsJ A Sekiguchi
Howard Hughes Medical Institute, Harvard University Medical School, Boston, MA 02115, USA
Mol Cell 8:1383-90. 2001..These results suggest a potential role for the non-core regions in repressing potentially harmful transposition events...
- Adoptive transfer of a superantigen-induced hole in the repertoire of natural IgM-secreting cellsG J Silverman
Department of Medicine, University of California San Diego, La Jolla, California 92093 0663, USA
Cell Immunol 209:76-80. 2001..These studies clarify the cellular mechanisms responsible for B-cell superantigen-induced modification of the repertoires of in vivo polyclonal B-cell populations...
- Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair proteinQ H Phung
Laboratory of Molecular Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
J Exp Med 187:1745-51. 1998..The results suggest that the hypermutation pathway frequently mutates G.C pairs, and a MSH2-dependent pathway preferentially corrects mismatches at G and C...
- Antibody repertoires generated by VH replacement and direct VH to JH joiningSergei B Koralov
The CBR Institute for Biomedical Research, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
Immunity 25:43-53. 2006..Thus, V(H) replacement is an efficient mechanism of antibody diversification, and its impact on the overall antibody repertoire could be greater than anticipated because it frequently leaves no molecular footprint...
- Localization of recombination activating gene 1/green fluorescent protein (RAG1/GFP) expression in secondary lymphoid organs after immunization with T-dependent antigens in rag1/gfp knockin miceH Igarashi
Departments of Immunology, Pediatrics, and Cell Differentiation Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Japan
Blood 97:2680-7. 2001....
- Immunoglobulin heavy chain gene replacement: a mechanism of receptor editingC Chen
Department of Molecular Biology, Princeton University, New Jersey 08544, USA
Immunity 3:747-55. 1995..The sd-tg model thus provides direct evidence for secondary rearrangement at VH-D-JH. This process may play a role in tolerance by editing autoreactive receptors and may also serve to diversify the VH repertoire...
- Long-term cultured E2A-deficient hematopoietic progenitor cells are pluripotentTomokatsu Ikawa
Division of Biological Sciences, 0377 University of California, San Diego, La Jolla, CA 92093, USA
Immunity 20:349-60. 2004..These observations indicate that E2A-deficient hematopoietic progenitor cells remain pluripotent after long-term culture in vitro and that E2A proteins play a critical role in B cell commitment...
- Both E12 and E47 allow commitment to the B cell lineageG Bain
Department of Biology, University of California, San Diego, La Jolla 92093, USA
Immunity 6:145-54. 1997..Taken together, the data indicate that both E12 and E47 allow commitment to the B cell lineage and act synergistically to promote B lymphocyte maturation...
- Inducible DNA breaks in Ig S regions are dependent on AID and UNGCarol E Schrader
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655, USA
J Exp Med 202:561-8. 2005..Our results indicate that AID attacks cytosines on both DNA strands, and staggered breaks are processed to blunt DSBs at the initiating ss break sites. We propose a model to explain the types of end-processing events observed...
- Identification and utilization of arbitrary correlations in models of recombination signal sequencesLindsay G Cowell
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
Genome Biol 3:RESEARCH0072. 2002..The method places no restrictions on the number of correlated positions or on their spatial relationship within the site. No prior empirical evidence for the correlation structure is necessary...
- EBV-infected B cells in infectious mononucleosis: viral strategies for spreading in the B cell compartment and establishing latencyJ Kurth
Institute for Genetics and Department of Internal Medicine I, University of Cologne, Germany
Immunity 13:485-95. 2000....
- The NF-kappaB canonical pathway is involved in the control of the exonucleolytic processing of coding ends during V(D)J recombinationM Margarida Souto-Carneiro
Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892 1560, USA
J Immunol 180:1040-9. 2008..However, selection of the primary B cell repertoire appeared to be intact and was partially able to correct the defects generated by abnormal V(D)J recombination...
- Role of receptor editing and revision in shaping the B and T lymphocyte repertoireV Kouskoff
Mount Sinai Hospital, Institute of Gene Therapy, New York, New York 10029, USA
Life Sci 69:1105-13. 2001..Recent studies have likewise suggested a role for receptor editing and revision in shaping the T cell repertoire during development and tolerance...
- Allelic exclusion of immunoglobulin gene rearrangement and expression: why and how?Mark Schlissel
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 3200, USA
Semin Immunol 14:207-212; discussion 225-6. 2002..This review will suggest an hypothesis to answer the 'why bother' aspect of allelic exclusion and then go on to propose a mechanism, distinct from feedback regulation, which may contribute to the allelic exclusion of Ig gene expression...
- The role of components of recombination signal sequences in immunoglobulin gene segment usage: a V81x modelM Larijani
Department of Immunology and Ontario Cancer Institute, University of Toronto, Room 8 111, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada
Nucleic Acids Res 27:2304-9. 1999..Furthermore, the contribution of the heptamer and nonamer to differential VHusage in our assay is correlated inversely with their conservation throughout the VHlocus...
- Rearrangement-enhancing element upstream of the mouse immunoglobulin kappa chain J clusterL Ferradini
INSERM U373, Institut Necker, Faculte de Medecine, Universite Paris V, France
Science 271:1416-20. 1996..This cis-acting recombination-enhancing element affects the rearrangement process without being involved in regulating transcription...
- B-cell repertoire formation: role of the recombination signal sequence in non-random V segment utilizationA J Feeney
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA
Immunol Rev 175:59-69. 2000..We also describe experiments showing that the sequence of the spacer of the RSS can play an important role in relative recombination frequencies...
- Use of immunoglobulin variable-region genes by normal subjects and patients with systemic lupus erythematosusA Hansen
Outpatients Clinic, Berlin, Germany
Int Arch Allergy Immunol 123:36-45. 2000....
- Improved methods for detecting selection by mutation analysis of Ig V region sequencesUri Hershberg
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
Int Immunol 20:683-94. 2008..These results show that selection can be detected in vivo with high specificity using the new method proposed here, allowing greater insight into the existence and direction of antigen-driven selection...
- Targeted disruption of the Artemis murine counterpart results in SCID and defective V(D)J recombination that is partially corrected with bone marrow transplantationLanying Li
Department of Pediatrics, University of California, San Francisco, CA 94143, USA
J Immunol 174:2420-8. 2005....
- Anti-peripherin B lymphocytes are positively selected during diabetogenesisJorge Carrillo
Laboratory of Immunobiology for Research and Application to Diagnosis and Center for Transfusion and Tissue Bank BST, Institut d Investigacio Germans Trias i Pujol, Badalona, Barcelona, Spain
Mol Immunol 45:3152-62. 2008....
- Mice reconstituted with DNA polymerase beta-deficient fetal liver cells are able to mount a T cell-dependent immune response and mutate their Ig genes normallyG Esposito
Institute for Genetics, University of Cologne, D 50931 Cologne, Germany
Proc Natl Acad Sci U S A 97:1166-71. 2000....
- Lack of N regions in antigen receptor variable region genes of TdT-deficient lymphocytesT Komori
Howard Hughes Medical Institute, Children s Hospital, Boston, MA 02115
Science 261:1171-5. 1993....
- Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MSDoris Lambracht-Washington
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
J Neuroimmunol 186:164-76. 2007..Targeting the mechanisms that allow these self-reactive B cells to reside in the CSF of MS patients may prove to be a potent immunotherapeutic strategy...
- Utilization of polymerase chain reaction on archival cytologic material: a comparison with fresh material with special emphasis on cerebrospinal fluidsRubina Mattu
Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA
Mod Pathol 17:1295-301. 2004..SSL of archival cytologic material can be used with excellent results for molecular diagnostic tests when fresh material is not available or when the cytologic diagnosis needs further clarification...
- The chicken B-cell receptor complex and its role in avian B-cell developmentC E Sayegh
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
Immunol Rev 175:187-200. 2000....
- Rectification of age-related impairment in Ig gene hypermutation during a memory responseShuhua Han
Department of Immunology, Baylor College of Medicine, Houston, TX 77030, USA
Int Immunol 16:525-32. 2004..These findings may have important implications in designing vaccines and immunization protocols for the elderly population and patients with certain immune deficiencies such as AIDS...
- RAGs and regulation of autoantibodiesMila Jankovic
Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10021, USA
Annu Rev Immunol 22:485-501. 2004..Here we review the prevalence of autoantibodies in the initial antibody repertoire, their regulation by receptor editing, and the role of the recombinase proteins (RAG1 and RAG2) in this process...
- V(D)J recombination frequencies can be profoundly affected by changes in the spacer sequenceAlina Montalbano
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
J Immunol 171:5296-304. 2003..These data demonstrate that the spacer sequence should be considered to play an important role in the recombination efficacy of an RSS, and that the effect of the spacer occurs primarily subsequent to RAG binding...
- Nucleic acid structures and enzymes in the immunoglobulin class switch recombination mechanismKefei Yu
Department of Pathology, Norris Comprehensive Cancer Ctr, Rm 5428, 1441 Eastlake Ave, MC9176, Los Angeles, CA 90033, USA
DNA Repair (Amst) 2:1163-74. 2003..Progress has been made on the enzymes involved in leading to the DNA cleavage events and on identifying the unusual DNA structures that those enzymes recognize...
- Cell biology, molecular embryology, Lamarckian and Darwinian selection as evolvabilityH Hoenigsberg
Instituto de Genetica Evolutiva y Biologia Molecular, Universidad Manuela Beltran, Bogota, DC, Colombia
Genet Mol Res 2:7-28. 2003..It seems that molecular Lamarckism can survive (Lewin, 1993)...
- Antibody diversification by somatic mutation: from Burnet onwardsMichael S Neuberger
1Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
Immunol Cell Biol 86:124-32. 2008....
- Nonoverlapping functions of DNA polymerases mu, lambda, and terminal deoxynucleotidyltransferase during immunoglobulin V(D)J recombination in vivoBarbara Bertocci
INSERM U783, Faculté de Médecine René Descartes, Site Necker Enfants Malades, 156 rue de Vaugirard, 75730 Paris Cedex 15, France
Immunity 25:31-41. 2006....
- Mice lacking TdT: mature animals with an immature lymphocyte repertoireS Gilfillan
Laboratoire de Genetique Moleculaire des Eucaryotes du CNRS, Institut de Chimie Biologique, Strasbourg, France
Science 261:1175-8. 1993..Thus, switch-on of the TdT gene during the first week after birth provokes an even greater expansion of lymphocyte receptor diversity than had previously been thought...
- Homology-directed recombination in IgH variable region genes from human neonates, infants and adults: implications for junctional diversityKarl Bauer
Department of Pediatrics, JW Goethe University, Frankfurt, Germany
Mol Immunol 44:2969-77. 2007..Therefore, unlike in mice, homology-directed recombination does not cause junctional uniformity in human neonates...
- Allelic 'choice' governs somatic hypermutation in vivo at the immunoglobulin kappa-chain locusShira Fraenkel
The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel
Nat Immunol 8:715-22. 2007..Thus, it seems that the epigenetic mechanisms that initially bring about monoallelic variable-(diversity)-joining rearrangement continue to be involved in the control of antibody diversity at later stages of B cell development...
- Primary cutaneous lymphoproliferative disorders with dual lineage rearrangementDmitry V Kazakov
Sikl s Department of Pathology, Charles University, Medical Faculty Hospital, Pilsen, Czech Republic
Am J Dermatopathol 28:399-409. 2006..Further reports are needed to identify these lesions to clarify their nature and biologic potential...
- Accessibility control of V(D)J recombinationRobin Milley Cobb
Department of Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
Adv Immunol 91:45-109. 2006..The discussion will focus on cis-acting regulation by ACEs, the nuclear factors that control ACE function, and the epigenetic modifications that establish recombinase accessibility...
- Normal D-JH rearranged products of the IgH gene in SCID mouse bone marrowR Araki
Cell Biology Laboratory, Department of Radiobiology, Radiation Effects Research Foundation, 8 6 Nakagawa 1 chome, Nagasaki 850, Japan
Int Immunol 8:1045-53. 1996..Furthermore, the features of rearranged products isolated from SCID bone marrow cells were remarkably similar to those from leaky SCID mice...
- V(D)J recombination activates a p53-dependent DNA damage checkpoint in scid lymphocyte precursorsC J Guidos
Division of Immunology and Cancer, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
Genes Dev 10:2038-54. 1996..These results demonstrate that a p53-mediated DNA damage checkpoint contributes to the immune deficiency characteristic of the scid mutation and limits the oncogenic potential of DSBs generated during V(D)J recombination...
- Frequent occurrence of B-cell lymphomas in angioimmunoblastic T-cell lymphoma and proliferation of Epstein-Barr virus-infected cells in early casesKlaus Willenbrock
Senckenbergisches Institut für Pathologie, Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main, Frankfurt am Main, Germany
Br J Haematol 138:733-9. 2007..This might be relevant in the development of secondary lymphomas...
- Two consecutive immunophenotypic switches in a child with MLL-rearranged acute lymphoblastic leukemiaGiuseppe Germano
Laboratory of Pediatric Onco Hematology, Department of Pediatrics, University Hospital of Padua, Padua, Italy
Haematologica 91:ECR09. 2006..The high expression of HOXA9 and FLT3 genes remaining genotypically stable in a leukemia throughout phenotypic switches, suggests that this leukemia may have originated as a common B/myeloid progenitors...
- Acetylation increases access of remodelling complexes to their nucleosome targets to enhance initiation of V(D)J recombinationKarl P Nightingale
Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
Nucleic Acids Res 35:6311-21. 2007....
- The analysis and quantification of a clonal B cell response in a hyperimmunized anti-D donorS E Dohmen
Sanquin Research, Amsterdam and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, 10066 CX Amsterdam, The Netherlands
Clin Exp Immunol 144:223-32. 2006..Furthermore, we found a high frequency of clonal B cells. These results contribute to the understanding of the immune response against RhD in hyperimmunized anti-D donors...
- Immunoglobulin light chain gene rearrangements in precursor-B-acute lymphoblastic leukemia: characteristics and applicability for the detection of minimal residual diseaseVincent H J van der Velden
Department of Immunology, Erasmus MC, Rotterdam, The Netherlands
Haematologica 91:679-82. 2006..Our data show that Vk-Jk and Vlambda-Jlambda rearrangements can be successfully applied for MRD detection in a subset of patients with precursor-B-ALL...
- Regulation of IgH gene assembly: role of the intronic enhancer and 5'DQ52 region in targeting DHJH recombinationRoshi Afshar
Department of Microbiology Immunology, Vanderbilt University Medical School, Nashville, TN 37232, USA
J Immunol 176:2439-47. 2006....
- Rearrangement/hypermutation/gene conversion: when, where and why?J C Weill
INSERM U373, Faculte de Medecine Necker, Enfants Malades, Universite Paris, France
Immunol Today 17:92-7. 1996..They propose that somatic mutation and gene conversion represent analogous molecular strategies occurring in specific chromatin accessibility contexts...
- Human B cells accumulate immunoglobulin V gene somatic mutations in a cell contact-dependent manner in cultures supported by activated T cells but not in cultures supported by CD40 ligandS C Huang
Virginia Mason Research Center Department of Immunology, University of Washington, Seattle, WA, USA
Clin Exp Immunol 116:441-8. 1999..Cell-cell contact was required for mutation because mutations were not detected when B cells were separated from activated T cells by a membrane...
- Molecular immunoglobulin/T- cell receptor clonality analysis in cutaneous lymphoproliferations. Experience with the BIOMED-2 standardized polymerase chain reaction protocolYorick Sandberg
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Haematologica 88:659-70. 2003..The obtained PCR products were subjected to heteroduplex (HD) and GeneScan (GS) analysis. We compared the data of 154 samples with the histopathologic diagnosis, based on the EORTC classification of skin lymphomas...
- Comparative analyses of immunoglobulin genes: surprises and portentsMartin F Flajnik
Department of Microbiology and Immunology, University of Maryland at Baltimore, Baltimore, Maryland 21201, USA
Nat Rev Immunol 2:688-98. 2002....
- Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemiaLiguang Chen
Division of Hematology Oncology, Department of Medicine, University of California, San Diego for the CLL Research Consortium, San Diego, CA, USA
Blood 100:4609-14. 2002....
- V(D)J recombinatorial repertoire diversification during intraclonal pro-B to B-cell differentiationYui Hsi Wang
Division of Developmental and Clinical Immunology, and Department of Medicine, University of Alabama at Birmingham and the Howard Hughes Medical Institute, Birmingham, AL 35294, USA
Blood 101:1030-7. 2003..These findings validate the principle of intraclonal V(D)J diversification during B-cell generation and define a manipulable model of human B-cell differentiation...
- B cell development and proliferation of mature B cells in human fetal intestineSarah Golby
Department of Histopathology, GKT Medical School, St Thomas Campus, London, United Kingdom
J Leukoc Biol 72:279-84. 2002..Distinguishing characteristics of Ig lambda genes in postnatal gut were also studied in the fetus. According to these parameters, fetal and postnatal B cells are unrelated...
- Development of B cells in scid mice with immunoglobulin transgenes: implications for the control of V(D)J recombinationY Chang
Fox Chase Cancer Center, Institute for Cancer Research, Philadelphia, Pennsylvania 19111, USA
Immunity 2:607-16. 1995..This rescue of scid B cell differentiation is associated with a dramatic reduction in expression of the recombination activation genes, RAG1 and RAG2, and with reduced transcription of the kappa locus...
- Features of the overexpressed V1-69 genes in the unmutated subset of chronic lymphocytic leukemia are distinct from those in the healthy elderly repertoireKathleen N Potter
Molecular Immunology Group, Tenovus Laboratory, Southampton University Hospitals Trust, Southampton, United Kingdom
Blood 101:3082-4. 2003..These findings support the concept that CLL arises from B cells driven by antigen/superantigen and is not a stochastic event in the elderly B-cell population...
- Role of receptor revision in forming a B cell repertoireJane Seagal
Department of Immunology, Bruce Rappaport Faculty of Medicine and Rappaport Family Institute for Research in the Medical Sciences, Technion Israel Institute of Technology, Haifa 31096, Israel
Clin Immunol 105:1-8. 2002
- Clues to the etiology of autoimmune diseases through analysis of immunoglobulin genesJason M Link
Department of Microbiology, Division of Developmental and Clinical Immunology, Wallace Tumor Institute 378, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294, USA
Arthritis Res 4:80-3. 2002....
- Salivary gland B cell lymphoproliferative disorders in Sjögren's syndrome present a restricted use of antigen receptor gene segments similar to those used by hepatitis C virus-associated non-Hodgkins's lymphomasValli De Re
Division of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCS, Aviano, Italy
Eur J Immunol 32:903-10. 2002....
- Somatic immunoglobulin hypermutationMarilyn Diaz
Department of Immunology, Imm16, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Curr Opin Immunol 14:235-40. 2002..The nature of the targeting mechanism and the trans-factors effecting such breaks and their repair remain to be determined...
- Antibody repertoire development in fetal and neonatal piglets. VI. B cell lymphogenesis occurs at multiple sites with differences in the frequency of in-frame rearrangementsMarek Sinkora
Department of Immunology and Gnotobiology, Institute of Microbiology, Czech Academy of Sciences, Doly 183, 549 22 Novy Hradek, Czech Republic
J Immunol 170:1781-8. 2003..We propose the latter to result from differential selection or a developmentally dependent change in the intrinsic mechanism of VDJ rearrangement...
- Ligand-dependent and -independent processes in B-cell-receptor-mediated signalingE M Fuentes-Pananá
University of Pennsylvania School of Medicine, Room 311 BRBII III, 421 Curie Blvd, Philadelphia, PA 19104, USA
Springer Semin Immunopathol 23:333-50. 2001..Here we discuss the evidence for ligand-independent functions for the BCR and postulate how it may be regulated and linked to biological processes associated with B cell development and survival...
- Modifications of histone cores and tails in V(D)J recombinationKathrin Muegge
Laboratory of Molecular Immunoregulation, SAIC Basic Science Program, National Cancer Institute, Frederick, MD 21701, USA
Genome Biol 4:211. 2003..A recent study shows that methylated lysine 79 in the core region of histone H3 also plays a role by providing a euchromatic 'mark' that may regulate access of the V(D)J recombinase...
- B cells in epithelial and perivascular compartments of human adult thymusK G Flores
Department of Pathology and the Cell and Molecular Biology Program, Duke University Medical Center, Durham, NC 27710, USA
Hum Pathol 32:926-34. 2001....
- Epstein-Barr virus (EBV)-positive lymphoproliferations in post-transplant patients show immunoglobulin V gene mutation patterns suggesting interference of EBV with normal B cell differentiation processesAndreas Bräuninger
Department of Pathology, University of Frankfurt, Germany
Eur J Immunol 33:1593-602. 2003....
- The VH gene repertoire of splenic B cells and somatic hypermutation in systemic lupus erythematosusNicola L W Fraser
Division of Immunology, Infection and Inflammation, University of Glasgow, Western Infirmary, Glasgow, Scotland, UK
Arthritis Res Ther 5:R114-21. 2003..This is the first study of the splenic GC response in human SLE...
- [Primers for detecting gene rearrangement in different regions of immunoglobulin heavy chain genes and their application in diagnosis of paraffin-embedded lymphoma tissues]Zong Li Qi
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
Nan Fang Yi Ke Da Xue Xue Bao 28:1964-7. 2008....
- A six-year-old boy with a suspicious thyroid nodule: intrathyroidal thymic tissueCarlos Hernandez-Cassis
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism University of Miami Miller School of Medicine, Miami, Florida, USA
Thyroid 18:377-80. 2008..Ectopic intrathyroidal thymus tissue that forms mass lesions as a consequence of aberrant thymic migration during embryogenesis is rarely reported in the literature...
- Assessment of BAFF as a mucosal HIV DNA vaccine adjuvantDavid Nemazee; Fiscal Year: 2005....
- Immune Tolerance in Non-clonal Immune SystemsDavid Nemazee; Fiscal Year: 2003..These studies should have broad applications to questions of lymphocyte activation, differentiation, and survival. ..
- Manipulating the IgE response with IgE-reactive macroself antigenDavid Nemazee; Fiscal Year: 2007..Furthermore, IgE macroself Ag-mediated suppression by gene transfer will be assessed both during and after antigenic sensitization. [unreadable] [unreadable]..
- Effect of BAFF on threshold of B cell toleranceDavid Nemazee; Fiscal Year: 2010..The long-term goal of these studies is to understand how BAFF promotes Sjogren's Syndrome and to determine the basic parameters regulating immune tolerance. ..
- B LYMPHOCYTE TOLERANCE IN HEALTH AND AUTOIMMUNITYDavid Nemazee; Fiscal Year: 2009....
- RECEPTOR EDITING IN B CELLSDavid Nemazee; Fiscal Year: 2010..ARRA Response:2 R01 A1033608-16A1 ARRA Response: 2 ROl A1033608-16A1 F-- protein GSK3$3 is poorly activated by BCR signaling in immature B cells. L-' ..
- IMMUNOGLOBULIN V GENES AND B CELL DEVELOPMENTRichard Hardy; Fiscal Year: 2006..The results of these studies will help to establish the types of selection that shape the expressed B cell repertoire, both fetally and in the adult, with implications for modulating normal and autoimmune responses. ..
- BD Biosciences LSR Flow CytometerRichard Hardy; Fiscal Year: 2002..abstract_text> ..
- Receptor Editing in Autoimmune and Normal MiceANN FEENEY; Fiscal Year: 2009..The information gained in these aims should give insights into the response of the various Ig loci to receptor editing signals, and how these processes may potentially be misregulated in B cells of autoimmune mice. ..
- THE ROLE OF COMPLEMENT IN AUTOIMMUNITYGarnett Kelsoe; Fiscal Year: 2005..Thus, we propose that the innate immune system controls both the frequency of peripheral, self-reactive B cells and their exposure to antigen. ..
- RHEUMATIC DISEASES CORE CENTERGregg Silverman; Fiscal Year: 2006..An Administrative Core (PI-G.J. Silverman, Center Director) will provide overall direction and supervision to all Center programs through an Executive Committee, which will be assisted by an Outside Advisory Committee. ..
- B CELL REPERTOIRE FORMATIONANN FEENEY; Fiscal Year: 2009..Together, these studies should give insight into the epigenetic mechanisms and cis-elements which control VH gene rearrangement in fetal and adult pro-B cells. ..
- B CELL SUPERANTIGENS AND IMMUNE REGULATIONGregg Silverman; Fiscal Year: 2008..In addition, these studies will lead to a better understanding of the immunobiologic activities of a virulence factor from one of the most important causes of life-threatening infection in the US. ..
- Arthritis Research Conference 2005Gregg Silverman; Fiscal Year: 2005..abstract_text> ..
- Arthritis Research Conference 2007Gregg Silverman; Fiscal Year: 2007..unreadable] [unreadable] [unreadable] [unreadable]..
- MOLECULAR ANALYSIS OF THE ANTIH INFLUENZAE RESPONSEANN FEENEY; Fiscal Year: 2001..We will also further analyze the diversity in the ani-hib response through the use of combinatorial libraries, correlating affinity with the Vh, Vk and CDR3's which are used. ..
- Cell Death and Antibody-Mediated Protection from AutoimmunityGREGG JOSHUA SILVERMAN; Fiscal Year: 2010....
- ANALYSIS OF THE MURINE ANTIBODY REPERTOIREGARNETT H KELSOE; Fiscal Year: 2010..Qom cap mop axiom 0-c 0opccc woo'- t00 0co -td ..
- Mechanisms to Induce Protective Natural AutoimmunityGregg Silverman; Fiscal Year: 2004..abstract_text> ..
- alpha4beta1 Intergrin Signaling In Immunity And ArthritisGREGG JOSHUA SILVERMAN; Fiscal Year: 2010..Collectively, this work will provide insight into the role of the ct4-paxillin interaction in inflammation and immunity, and whether this interaction is a potential bona fide therapeutic target for arthritis. ..
- Control of Accessibility for V(D) J RecombinationANN FEENEY; Fiscal Year: 2006..We will determine if other transcription factors such as Pax5 or Btk will induce rearrangement of other Ig loci, such as Vh or lambda. ..
- Characterization of V(D)J cleavage and repair complexesPATRICK SWANSON; Fiscal Year: 2007..abstract_text> ..
- The role of PKK in NFkappa B activationShiv Pillai; Fiscal Year: 2007..PKK represents a novel enzyme that may be critical in pathways that are important in cancer, inflammation, cell survival, and differentiation. ..
- Molecular basis of the requirements for IRF4 and IRF8 in pre-B cell developmentRunqing Lu; Fiscal Year: 2010..In the absence of IRF4,8, pro-B cell development appears to be normal but pre-B cell development is blocked. We hypothesize that expression of IRF4,8 is induced at the pre-B stage by pre-BCR though Blnk/Btk-mediated signaling. ..
- Gene Repression in Fragile X SyndromeHoward Cedar; Fiscal Year: 2006..abstract_text> ..
- The role of Immunoglobulin CDRH3 in Autoimmune DiseaseHARRY WILLIAM SCHROEDER; Fiscal Year: 2010....
- Differential GVHD induction by naive and memory T cellsMark Shlomchik; Fiscal Year: 2009..These studies can clearly help set the stage for applying this approach in rationally designed clinical pilot studies. ..
- DNA Breaks in Class Switch RecombinationCAROL SCHRADER; Fiscal Year: 2009..Enzymes from the BER pathway will be used to treat genomic DNA from B cells induced to switch in order to detect intermediates in the repair pathway that are predicted by this model. ..
- DNA REPLICATION IN ANIMAL CELLSHoward Cedar; Fiscal Year: 2009....
- Molecular identification of a sialyl 9-O-acetyl transferaseShiv Pillai; Fiscal Year: 2008..The gene that codes for an enzyme that controls the strength of the immune response will be studied. This gene may be an important target for the treatment of lupus and other related diseases. [unreadable] [unreadable] [unreadable]..
- IMMUNOREGULATION OF MURINE CD8+ T CELLSPamela Fink; Fiscal Year: 2009..abstract_text> ..
- ONTOGENY AND PHYLOGENY OF THE MHCMartin Flajnik; Fiscal Year: 2009..tropicalis), we will begin to analyze the modes of silencing in the tetraploids and eventually the higher order octo- and dodecaploid individuals. ..
- MOUSE MODELS TO STUDY THE ROLE OF TRAF1 AND TRAF2 IN THE ETIOLOGY OF LEUKEMIAJuan Zapata; Fiscal Year: 2007..Characterization of the CLL-like lymphoproliferative disorder caused by overexpression of TRAF2DN and Bcl-2 in B cells. [unreadable] [unreadable] [unreadable] [unreadable]..
- B LYMPHOCYTE INDUCED MATURATION PROTEINKathryn Calame; Fiscal Year: 2007..We will purify Blimp-1-containing repression complexes and identify the components of the complexes. ..
- Pathogenesis of Notch LeukemiaJon Aster; Fiscal Year: 2007..1. To identify domains of MAML1 that are essential for function in normal and transformed lymphoid cells 3.2. To identify and characterize small molecule inhibitors of CSL/ICN/MAML1 function ..
- Testing in Vivo Roles of TLRs in Systemic AutoimmunityMark Shlomchik; Fiscal Year: 2004..Because TLR9 is already strongly implicated in the activation of RF B cells in vitro and also by emerging data in vivo, we will focus on the role of this receptor on B cells. ..
- Highly Stable, Anthrax-specific Shark Antibody FragmentMartin Flajnik; Fiscal Year: 2004....
- Marginal zone B lymphocytes and blood borne pathogensShiv Pillai; Fiscal Year: 2004..Finally we will attempt to determine whether antigen-specific MZ B cells, as opposed to follicuar B cells, can readily capture and present blood borne antigens, and thus activate na'fve T cells. ..
- TCRb CDR3 and Susceptibility to Autoimmune DiseaseHarry Schroeder; Fiscal Year: 2003..These experiments will also shed light on the role of potentially abnormal TCR sequence in promoting lupus and other autoimmune diseases. ..
- Anti-Sm B-1 Cell Differentiation and FunctionStephen Clarke; Fiscal Year: 2003..In the final aim, the fate of B cells that normally differentiate to B-l will be determined in autoimmune MRL/lpr mice using a Tg model system of B-l differentiation. ..
- TRANSCRIPTION OF IMMUNOGLOBULIN HEAVY CHAIN GENESKathryn Calame; Fiscal Year: 2001....
- MoFlo High Speed Fluorescence Activated Cell SorterMark Shlomchik; Fiscal Year: 2003..Twenty-four NIH-funded researchers would benefit from this instrument at YSM. Several young investigators not yet NIH-funded would also benefit. ..
- Pre-BCR expression level regulates cellular functionsStephen Clarke; Fiscal Year: 2002..In the final aim whether the basis for the inability of 8/GO Tg mice to generate immature B cells is due to a pre-BCR or BCR deficiency will be determined. ..
- Activation and Regulation of Rheumatoid Factor B cellsMark Shlomchik; Fiscal Year: 2002..abstract_text> ..
- DEVELOPMENT OF THE ANTIBODY REPERTOIREHarry Schroeder; Fiscal Year: 2005..Finally, the effect that alteration of HCDR3 has on the development of the natural autoantibody repertoire and on the progression of autoimmune disease in the MRL-lpr/lpr mouse will be examined. ..
- Studies on human peripheral B lymphocytesShiv Pillai; Fiscal Year: 2005....
- Analyzing VDJ recombination at the single molecule levelDavid Roth; Fiscal Year: 2005....
- LSRII Flow Cytometric AnalyzerMark Shlomchik; Fiscal Year: 2007..of 27 NIH-funded PIs who require sophisticated FACS analysis and specific features of the LSRII, which otherwise may not be available due to limited capacity or capability of our existing machine [unreadable] [unreadable] [unreadable]..
- Anti-Sm B Cell RegulationStephen Clarke; Fiscal Year: 2007..In addition, we will test the hypothesis that the unusual pattern of CD 19 expression affects tolerance and activation. ..
- Targeting of somatic hypermutation and gene conversionDavid Schatz; Fiscal Year: 2006..The results of these experiments should set the stage for significant progress toward an understanding of the mechanism by which protein factors and DNA sequences collaborate to target SM and GC to Ig genes. ..
- IMMUNOGLOBULIN AND T CELL RECEPTOR GENE ASSEMBLYDavid Schatz; Fiscal Year: 2006..Overall, our experiments will address both the targeting and rejoining functions of the RAG proteins, with the long term goal of linking these fundamental activities to chromosomal translocations found in human malignancies. ..
- Role and Regulation of BLIMP-1 in Myeloid CellsKathryn Calame; Fiscal Year: 2006..Finally, the signals and mechanisms responsible for regulation of Blimp-1 expression in myeloid cells will be studied. ..
- TRANSCRIPTION AND MODIFICATION OF CHROMATIN DNAHoward Cedar; Fiscal Year: 2005..abstract_text> ..
- MOUSE MODELS TO STUDY MULIBREY NANISMJuan Zapata; Fiscal Year: 2005..study the developmental and phenotypic alterations of trim37 knock out and FINmajor-mutated trim37 mice. These mice will be the foundation for further studies on the biology and etiology of Mulibrey Nanism. ..
- PHENOTYPIC ANALYSES OF RECENT THYMIC EMIRGRANTS IN MICEPamela Fink; Fiscal Year: 2005..The overall goal of this work is to understand how thymic output and post thymic maturation vary with age, with an eye toward modulating immune senescence and recovery from lymphoablative therapies and diseases. ..
- Patterns of gene expression in Mulibrey NanismJuan Zapata; Fiscal Year: 2005..Specific Aim 2, is there any alteration in the patterns of gene expression induced by cytokines in normal and Mulibrey Nanism fibroblasts? Specific Aim 3, what is the role of TRIM37 in regulating gene expression? ..
- MEMBRANE IMMUNOGLOBULIN ASSEMBLY AND FUNCTIONShiv Pillai; Fiscal Year: 2002..Since the majority of human lymphomas develop form activated B-cells, these signaling mechanisms are likely to be of direct relevance for a significant proportion of human cancers. ..