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  1. Article ; Online: Mutation of the IFNAR-1 receptor binding site of human IFN-alpha2 generates type I IFN competitive antagonists.

    Pan, Manjing / Kalie, Eyal / Scaglione, Brian J / Raveche, Elizabeth S / Schreiber, Gideon / Langer, Jerome A

    Biochemistry

    2008  Volume 47, Issue 46, Page(s) 12018–12027

    Abstract: Type I interferons (IFNs) are multifunctional cytokines that activate cellular responses by binding a common receptor consisting of two subunits, IFNAR-1 and IFNAR-2. Although the binding of IFNs to IFNAR-2 is well characterized, the binding to the lower ...

    Abstract Type I interferons (IFNs) are multifunctional cytokines that activate cellular responses by binding a common receptor consisting of two subunits, IFNAR-1 and IFNAR-2. Although the binding of IFNs to IFNAR-2 is well characterized, the binding to the lower affinity IFNAR-1 remains less well understood. Previous reports identified a region of human IFN-alpha2 on the B and C helices ("site 1A": N65, L80, Y85, Y89) that plays a key role in binding IFNAR-1 and contributes strongly to differential activation by various type I IFNs. The current studies demonstrate that residues on the D helix are also involved in IFNAR-1 binding. In particular, residue 120 (Arg in IFN-alpha2; Lys in IFN-alpha2/alpha1) appears to be a "hot-spot" residue: substitution by alanine significantly decreased biological activity, and the charge-reversal mutation of residue 120 to Glu caused drastic loss of antiviral and antiproliferative activity for both IFN-alpha2 and IFN-alpha2/alpha1. Mutations in residues of helix D maintained their affinity for IFNAR-2 but had decreased affinity for IFNAR-1. Single-site or multiple-site mutants in the IFNAR-1 binding site that had little or no detectable in vitro biological activity were capable of blocking in vitro antiviral and antiproliferative activity of native IFN-alpha2; i.e., they are type I IFN antagonists. These prototype IFN antagonists can be developed further for possible therapeutic use in systemic lupus erythematosus, and analogous molecules can be designed for use in animal models.
    MeSH term(s) Amino Acid Substitution ; Animals ; Binding Sites/genetics ; Cattle ; Disease Models, Animal ; Humans ; Interferon-alpha/antagonists & inhibitors ; Interferon-alpha/chemistry ; Interferon-alpha/genetics ; Interferon-alpha/metabolism ; Lupus Erythematosus, Systemic/drug therapy ; Lupus Erythematosus, Systemic/genetics ; Lupus Erythematosus, Systemic/metabolism ; Mice ; Protein Binding/genetics ; Protein Structure, Secondary/genetics ; Receptor, Interferon alpha-beta/chemistry ; Receptor, Interferon alpha-beta/genetics ; Receptor, Interferon alpha-beta/metabolism
    Chemical Substances IFNAR1 protein, human ; IFNAR2 protein, human ; Ifnar1 protein, mouse ; Ifnar2 protein, mouse ; Interferon-alpha ; Receptor, Interferon alpha-beta (156986-95-7)
    Language English
    Publishing date 2008-11-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/bi801588g
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 217: Show issues Location:
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  2. Article ; Online: Correcting miR-15a/16 genetic defect in New Zealand Black mouse model of CLL enhances drug sensitivity.

    Salerno, Erica / Scaglione, Brian J / Coffman, Frederick D / Brown, Brian D / Baccarini, Alessia / Fernandes, Helen / Marti, Gerald / Raveche, Elizabeth S

    Molecular cancer therapeutics

    2009  Volume 8, Issue 9, Page(s) 2684–2692

    Abstract: Alterations in the human 13q14 genomic region containing microRNAs mir-15a and mir-16-1 are present in most human chronic lymphocytic leukemia (CLL). We have previously found the development of CLL in the New Zealand Black murine model to be associated ... ...

    Abstract Alterations in the human 13q14 genomic region containing microRNAs mir-15a and mir-16-1 are present in most human chronic lymphocytic leukemia (CLL). We have previously found the development of CLL in the New Zealand Black murine model to be associated with a point mutation in the primary mir-15a/16-1 region, which correlated with a decrease in mature miR-16 and miR-15a levels. In this study, addition of exogenous miR-15a and miR-16 led to an accumulation of cells in G(1) in non-New Zealand Black B cell and New Zealand Black-derived malignant B-1 cell lines. However, the New Zealand Black line had significantly greater G(1) accumulation, suggesting a restoration of cell cycle control upon exogenous miR-15a/16 addition. Our experiments showed a reduction in protein levels of cyclin D1, a miR-15a/16 target and cell cycle regulator of G(1)/S transition, in the New Zealand Black cell line following miR-15a/16 addition. These microRNAs were shown to directly target the cyclin D1 3' untranslated region using a green fluorescent protein lentiviral expression system. miR-16 was also shown to augment apoptosis induction by nutlin, a mouse double minute 2 (MDM2) antagonist, and genistein, a tyrosine kinase inhibitor, when added to a B-1 cell line derived from multiple in vivo passages of malignant B-1 cells from New Zealand Black mice with CLL. miR-16 synergized with nutlin and genistein to induce apoptosis. Our data support a role for the mir-15a/16-1 cluster in cell cycle regulation and suggest that these mature microRNAs in both the New Zealand Black model and human CLL may be targets for therapeutic efficacy in this disease.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Apoptosis ; Base Sequence ; Cyclin D1/genetics ; DNA Primers ; Disease Models, Animal ; Drug Screening Assays, Antitumor ; Genistein/therapeutic use ; Imidazoles/therapeutic use ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Mice ; Mice, Inbred C57BL ; MicroRNAs/genetics ; Piperazines/therapeutic use ; RNA, Messenger/genetics
    Chemical Substances Antineoplastic Agents ; DNA Primers ; Imidazoles ; MicroRNAs ; Piperazines ; RNA, Messenger ; Cyclin D1 (136601-57-5) ; nutlin 3 (53IA0V845C) ; Genistein (DH2M523P0H)
    Language English
    Publishing date 2009-09-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-09-0127
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5750: Show issues Location:
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  3. Article ; Online: Murine models of chronic lymphocytic leukaemia: role of microRNA-16 in the New Zealand Black mouse model.

    Scaglione, Brian J / Salerno, Erica / Balan, Murugabaskar / Coffman, Frederick / Landgraf, Pablo / Abbasi, Fatima / Kotenko, Sergei / Marti, Gerald E / Raveche, Elizabeth S

    British journal of haematology

    2007  Volume 139, Issue 5, Page(s) 645–657

    Abstract: Mouse models are valuable tools in the study of human chronic lymphocytic leukaemia (CLL). The New Zealand Black (NZB) strain is a naturally occurring model of late-onset CLL characterized by B-cell hyperproliferation and autoimmunity early in life, ... ...

    Abstract Mouse models are valuable tools in the study of human chronic lymphocytic leukaemia (CLL). The New Zealand Black (NZB) strain is a naturally occurring model of late-onset CLL characterized by B-cell hyperproliferation and autoimmunity early in life, followed by progression to CLL. Other genetically engineered models of CLL that have been developed include (NZB x NZW) F1 mice engineered to express IL5, mice expressing human TCL1A, and mice overexpressing both BCL2 and a tumour necrosis factor receptor-associated factor. The applicability to human CLL varies with each model, suggesting that CLL is a multifactorial disease. Our work with the de novo NZB model has revealed many similarities to the human situation, particularly familial CLL. In NZB, the malignant clones express CD5, zap-70, and have chromosomal instability and germline Ig sequence. We also identified a point mutation in the 3'-flanking sequence of Mirn16-1, which resulted in decreased levels of the microRNA, miR-16 in lymphoid tissue. Exogenous restoration of miR-16 to an NZB malignant B-1 cell line resulted in cell cycle alterations, suggesting that the altered expression of Mirn15a/16-1 is an important molecular lesion in CLL. Future studies utilizing the NZB mouse could ascertain the role of environmental triggers, such as low dose radiation and organic chemicals in the augmentation of a pre-existing propensity to develop CLL.
    MeSH term(s) Animals ; Base Sequence ; Disease Models, Animal ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Mice ; Mice, Inbred NZB ; Mice, Transgenic ; MicroRNAs/genetics ; Molecular Sequence Data ; Point Mutation ; RNA, Neoplasm/genetics
    Chemical Substances MicroRNAs ; RNA, Neoplasm
    Language English
    Publishing date 2007-10-17
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 80077-6
    ISSN 1365-2141 ; 0007-1048
    ISSN (online) 1365-2141
    ISSN 0007-1048
    DOI 10.1111/j.1365-2141.2007.06851.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The New Zealand black mouse as a model for the development and progression of chronic lymphocytic leukemia.

    Salerno, Erica / Yuan, Yao / Scaglione, Brian J / Marti, Gerald / Jankovic, Alexander / Mazzella, Fermina / Laurindo, Maria Fernanda / Despres, Daryl / Baskar, Sivasubramanian / Rader, Christoph / Raveche, Elizabeth

    Cytometry. Part B, Clinical cytometry

    2010  Volume 78 Suppl 1, Page(s) S98–109

    Abstract: Background: Similar to a subset of human patients who progress from monoclonal B lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL), New Zealand Black (NZB) mice have an age-associated progression to CLL. The murine disease is linked to a genetic ...

    Abstract Background: Similar to a subset of human patients who progress from monoclonal B lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL), New Zealand Black (NZB) mice have an age-associated progression to CLL. The murine disease is linked to a genetic abnormality in microRNA mir-15a/16-1 locus, resulting in decreased mature miR-15a/16.
    Methods: Spleens of aging NZB were analyzed for the presence of B-1 cells via flow cytometry and for the presence of a side population (SP) via the ability of cells to exclude Hoechst 33342 dye. The SP was assayed for the presence of hyperdiploid B-1 clones and for the ability to differentiate into B-1 cells in vitro and transfer disease in vivo. In addition, enhanced apoptosis of chemoresistant NZB B-1 cells was examined by restoring miR-16 levels in nutlin-treated cells.
    Results: Aging NZB mice develop a B-1 expansion and clonal development that evolves from MBL into CLL. An expansion in SP is also seen. Although the SP did contain increased cells with stem cell markers, they lacked malignant B-1 cells and did not transfer disease in vivo. Similar to B-1 cells, splenic NZB SP also has decreased miR-15a/16 when compared with C57Bl/6. Exogenous addition of miR-15a/16 to NZB B-1 cells resulted in increased sensitivity to nutlin.
    Conclusion: NZB serve as an excellent model for studying the development and progression of age-associated CLL. NZB SP cells do not seem to contain cancer stem cells, but rather the B-1 stem cell. NZB B-1 chemoresistance may be related to reduced miR-15a/16 expression.
    MeSH term(s) Age Factors ; Animals ; Apoptosis/drug effects ; Cell Separation ; Cell Survival ; Disease Models, Animal ; Disease Progression ; Female ; Flow Cytometry ; Imidazoles/pharmacology ; Immunophenotyping ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NZB ; Piperazines/pharmacology ; Spleen/drug effects ; Spleen/immunology ; Spleen/pathology
    Chemical Substances Imidazoles ; Piperazines ; nutlin 1
    Language English
    Publishing date 2010-09-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2099657-3
    ISSN 1552-4957 ; 1552-4949 ; 0196-4763
    ISSN (online) 1552-4957
    ISSN 1552-4949 ; 0196-4763
    DOI 10.1002/cyto.b.20544
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1688: Show issues Location:
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  5. Article: Regulatory T cells as central regulators of both autoimmunity and B cell malignancy in New Zealand Black mice.

    Scaglione, Brian J / Salerno, Erica / Gala, Kinisha / Pan, Manjing / Langer, Jerome A / Mostowski, Howard S / Bauer, Steven / Marti, Gerald / Li, Yu / Tsiagbe, Vincent K / Raveche, Elizabeth S

    Journal of autoimmunity

    2009  Volume 32, Issue 1, Page(s) 14–23

    Abstract: Regulatory T cells (Tregs) play an important role in protection against autoimmune disease and are also known to be potent inhibitors of anti-tumor immune responses. The New Zealand Black (NZB) mouse is a murine model for both autoimmune diseases, since ... ...

    Abstract Regulatory T cells (Tregs) play an important role in protection against autoimmune disease and are also known to be potent inhibitors of anti-tumor immune responses. The New Zealand Black (NZB) mouse is a murine model for both autoimmune diseases, since high levels of autoantibodies are present, and human CLL, due to the expansion of malignant B-1 cells. In this study, we examined the functional role of CD4(+)CD25(+) Foxp3(+) Tregs in these different manifestations. Flow cytometric analysis showed increased levels of Tregs in NZB mice compared to healthy C57Bl/6 controls. Aged NZB mice that have developed a B-1 cell malignancy identified as IgM(+)CD5(+), have the most pronounced increase in Tregs. Ex vivo treatment of splenocytes from NZB mice with IFN-alpha resulted in a decrease in the frequency of Tregs and malignant B-1 cells. In vivo treatment of both NZB and C57Bl/6 mice with poly (I:C), a potent inducer of IFN-alpha, also led to a decrease in the levels of Tregs and malignant B-1 cells (NZB only) while amplifying autoimmune manifestations. These results indicate that while high levels of Tregs found in NZB mice might suppress a more severe autoimmune disease, they may also contribute to the development of the B cell malignancy.
    MeSH term(s) Age Factors ; Animals ; Antibodies/blood ; Antibodies/immunology ; Antibodies/pharmacology ; Antibodies, Antinuclear/blood ; Ascitic Fluid/cytology ; Ascitic Fluid/immunology ; Autoimmune Diseases/immunology ; Autoimmune Diseases/pathology ; Autoimmunity/immunology ; B-Lymphocytes/cytology ; B-Lymphocytes/drug effects ; B-Lymphocytes/immunology ; Erythrocytes/immunology ; Forkhead Transcription Factors/genetics ; Immune Tolerance/immunology ; Interferon-alpha/blood ; Interferon-alpha/pharmacology ; Interferons/genetics ; Interferons/pharmacology ; Interleukin-10/blood ; Interleukin-10/genetics ; Interleukin-2 Receptor alpha Subunit/immunology ; Leukemia, B-Cell/immunology ; Leukemia, B-Cell/pathology ; Lymph Nodes/cytology ; Lymph Nodes/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NZB ; Poly I-C/pharmacology ; Spleen/cytology ; Spleen/drug effects ; Spleen/immunology ; T-Lymphocyte Subsets/cytology ; T-Lymphocyte Subsets/drug effects ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; T-Lymphocytes, Regulatory/cytology ; T-Lymphocytes, Regulatory/drug effects ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; ZAP-70 Protein-Tyrosine Kinase/genetics
    Chemical Substances Antibodies ; Antibodies, Antinuclear ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; Interferon-alpha ; Interleukin-2 Receptor alpha Subunit ; Interleukin-10 (130068-27-8) ; Interferons (9008-11-1) ; ZAP-70 Protein-Tyrosine Kinase (EC 2.7.10.2) ; Zap70 protein, mouse (EC 2.7.10.2) ; Poly I-C (O84C90HH2L)
    Language English
    Publishing date 2009-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639452-8
    ISSN 0896-8411
    ISSN 0896-8411
    DOI 10.1016/j.jaut.2008.10.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2368: Show issues Location:
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  6. Article: Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice.

    Raveche, Elizabeth S / Salerno, Erica / Scaglione, Brian J / Manohar, Vijaya / Abbasi, Fatima / Lin, Yi-Chu / Fredrickson, Torgny / Landgraf, Pablo / Ramachandra, Sumant / Huppi, Konrad / Toro, Jorge R / Zenger, Vincent E / Metcalf, Robert A / Marti, Gerald E

    Blood

    2007  Volume 109, Issue 12, Page(s) 5079–5086

    Abstract: New Zealand black (NZB) mice with autoimmune and B lymphoproliferative disease (B-LPD) are a model for human chronic lymphocytic leukemia (CLL). A genomewide linkage scan of the NZB loci associated with lymphoma was conducted in F1 backcrosses of NZB and ...

    Abstract New Zealand black (NZB) mice with autoimmune and B lymphoproliferative disease (B-LPD) are a model for human chronic lymphocytic leukemia (CLL). A genomewide linkage scan of the NZB loci associated with lymphoma was conducted in F1 backcrosses of NZB and a control strain, DBA/2. Of 202 mice phenotyped for the presence or absence of LPD, surface maker expression, DNA content, and microsatellite polymorphisms, 74 had disease. The CD5(+), IgM(+), B220(dim), hyperdiploid LPD was linked to 3 loci on chromosomes 14, 18, and 19 that are distinct from previously identified autoimmunity-associated loci. The region of synteny with mouse D14mit160 is the human 13q14 region, associated with human CLL, containing microRNAs mir-15a16-1. DNA sequencing of multiple NZB tissues identified a point mutation in the 3' flanking sequence of the identical microRNA, mir-16-1, and this mutation was not present in other strains, including the nearest neighbor, NZW. Levels of miR-16 were decreased in NZB lymphoid tissue. Exogenous miR-16 delivered to an NZB malignant B-1 cell line resulted in cell-cycle alterations and increased apoptosis. Linkage of the mir-15a/16-1 complex and the development of B-LPD in this spontaneous mouse model suggest that the altered expression of the mir-15a/16-1 is the molecular lesion in CLL.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Apoptosis/genetics ; B-Lymphocytes ; Cell Cycle/drug effects ; Cell Cycle/genetics ; Chromosomes, Human, Pair 13/genetics ; Chromosomes, Mammalian ; DNA/analysis ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Lymphoproliferative Disorders/genetics ; Mice ; Mice, Inbred NZB ; MicroRNAs/genetics ; MicroRNAs/pharmacology ; Point Mutation ; Polymorphism, Genetic ; Synteny/genetics
    Chemical Substances MicroRNAs ; Mirn16 microRNA, mouse ; DNA (9007-49-2)
    Language English
    Publishing date 2007-03-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2007-02-071225
    Database MEDical Literature Analysis and Retrieval System OnLINE

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