Oncogene Myc

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Michel C. Nussenzweig - One of the best experts on this subject based on the ideXlab platform.

  • the proto Oncogene Myc is required for selection in the germinal center and cyclic reentry
    2012
    Co-Authors: David Dominguezsola, Michel C. Nussenzweig, Gabriel D. Victora, Carol Y Ying, Ryan T Phan, Masumichi Saito
    Abstract:

    The molecular control of germinal center selection is still being determined. Dalla-Favera and colleagues show that the cell-cycle regulator c-Myc is essential for B cell selection and reentry into the germinal center.

  • the proto Oncogene Myc is required for selection in the germinal center and cyclic reentry
    2012
    Co-Authors: David Dominguezsola, Michel C. Nussenzweig, Gabriel D. Victora, Carol Y Ying, Ryan T Phan, Masumichi Saito
    Abstract:

    After antigenic challenge, B cells enter the dark zone (DZ) of germinal centers (GCs) to proliferate and hypermutate their immunoglobulin genes. Mutants with greater affinity for the antigen are positively selected in the light zone (LZ) to either differentiate into plasma and memory cells or reenter the DZ. The molecular circuits that govern positive selection in the GC are not known. We show here that the GC reaction required biphasic regulation of expression of the cell-cycle regulator c-Myc that involved its transient induction during early GC commitment, its repression by Bcl-6 in DZ B cells and its reinduction in B cells selected for reentry into the DZ. Inhibition of c-Myc in vivo led to GC collapse, which indicated an essential role for c-Myc in GCs. Our results have implications for the mechanism of GC selection and the role of c-Myc in lymphomagenesis.

Ryan T Phan - One of the best experts on this subject based on the ideXlab platform.

  • the proto Oncogene Myc is required for selection in the germinal center and cyclic reentry
    2012
    Co-Authors: David Dominguezsola, Michel C. Nussenzweig, Gabriel D. Victora, Carol Y Ying, Ryan T Phan, Masumichi Saito
    Abstract:

    The molecular control of germinal center selection is still being determined. Dalla-Favera and colleagues show that the cell-cycle regulator c-Myc is essential for B cell selection and reentry into the germinal center.

  • the proto Oncogene Myc is required for selection in the germinal center and cyclic reentry
    2012
    Co-Authors: David Dominguezsola, Michel C. Nussenzweig, Gabriel D. Victora, Carol Y Ying, Ryan T Phan, Masumichi Saito
    Abstract:

    After antigenic challenge, B cells enter the dark zone (DZ) of germinal centers (GCs) to proliferate and hypermutate their immunoglobulin genes. Mutants with greater affinity for the antigen are positively selected in the light zone (LZ) to either differentiate into plasma and memory cells or reenter the DZ. The molecular circuits that govern positive selection in the GC are not known. We show here that the GC reaction required biphasic regulation of expression of the cell-cycle regulator c-Myc that involved its transient induction during early GC commitment, its repression by Bcl-6 in DZ B cells and its reinduction in B cells selected for reentry into the DZ. Inhibition of c-Myc in vivo led to GC collapse, which indicated an essential role for c-Myc in GCs. Our results have implications for the mechanism of GC selection and the role of c-Myc in lymphomagenesis.

Gabriel D. Victora - One of the best experts on this subject based on the ideXlab platform.

  • the proto Oncogene Myc is required for selection in the germinal center and cyclic reentry
    2012
    Co-Authors: David Dominguezsola, Michel C. Nussenzweig, Gabriel D. Victora, Carol Y Ying, Ryan T Phan, Masumichi Saito
    Abstract:

    The molecular control of germinal center selection is still being determined. Dalla-Favera and colleagues show that the cell-cycle regulator c-Myc is essential for B cell selection and reentry into the germinal center.

  • the proto Oncogene Myc is required for selection in the germinal center and cyclic reentry
    2012
    Co-Authors: David Dominguezsola, Michel C. Nussenzweig, Gabriel D. Victora, Carol Y Ying, Ryan T Phan, Masumichi Saito
    Abstract:

    After antigenic challenge, B cells enter the dark zone (DZ) of germinal centers (GCs) to proliferate and hypermutate their immunoglobulin genes. Mutants with greater affinity for the antigen are positively selected in the light zone (LZ) to either differentiate into plasma and memory cells or reenter the DZ. The molecular circuits that govern positive selection in the GC are not known. We show here that the GC reaction required biphasic regulation of expression of the cell-cycle regulator c-Myc that involved its transient induction during early GC commitment, its repression by Bcl-6 in DZ B cells and its reinduction in B cells selected for reentry into the DZ. Inhibition of c-Myc in vivo led to GC collapse, which indicated an essential role for c-Myc in GCs. Our results have implications for the mechanism of GC selection and the role of c-Myc in lymphomagenesis.

Masumichi Saito - One of the best experts on this subject based on the ideXlab platform.

  • the proto Oncogene Myc is required for selection in the germinal center and cyclic reentry
    2012
    Co-Authors: David Dominguezsola, Michel C. Nussenzweig, Gabriel D. Victora, Carol Y Ying, Ryan T Phan, Masumichi Saito
    Abstract:

    The molecular control of germinal center selection is still being determined. Dalla-Favera and colleagues show that the cell-cycle regulator c-Myc is essential for B cell selection and reentry into the germinal center.

  • the proto Oncogene Myc is required for selection in the germinal center and cyclic reentry
    2012
    Co-Authors: David Dominguezsola, Michel C. Nussenzweig, Gabriel D. Victora, Carol Y Ying, Ryan T Phan, Masumichi Saito
    Abstract:

    After antigenic challenge, B cells enter the dark zone (DZ) of germinal centers (GCs) to proliferate and hypermutate their immunoglobulin genes. Mutants with greater affinity for the antigen are positively selected in the light zone (LZ) to either differentiate into plasma and memory cells or reenter the DZ. The molecular circuits that govern positive selection in the GC are not known. We show here that the GC reaction required biphasic regulation of expression of the cell-cycle regulator c-Myc that involved its transient induction during early GC commitment, its repression by Bcl-6 in DZ B cells and its reinduction in B cells selected for reentry into the DZ. Inhibition of c-Myc in vivo led to GC collapse, which indicated an essential role for c-Myc in GCs. Our results have implications for the mechanism of GC selection and the role of c-Myc in lymphomagenesis.

Grazia Ambrosini - One of the best experts on this subject based on the ideXlab platform.

  • abstract b29 differential effects of brd4 inhibition on uveal melanoma cells with gnaq 11 mutations
    2015
    Co-Authors: Grazia Ambrosini
    Abstract:

    Uveal melanoma (UM) represents the most common intraocular malignancy, and there are no effective treatments for this aggressive disease. Nearly 80% of UM is characterized by oncogenic mutations in G protein subunits Gnaq and Gna11, and 70% have extra copies of the Oncogene Myc. Chromatin regulators have become attractive targets for cancer therapy. In particular, the BET-bromodomain inhibitor JQ1 has shown selective inhibition of c-Myc expression, followed by the suppression of c-Myc-dependent target genes. Treatments of UM cell lines with JQ1 showed that the Gnaq/Gna11 mutant cells were the most sensitive to BET inhibition with induction of cell death, while the cells without the mutations underwent cell cycle arrest in G1. Microarray analysis of UM cells revealed that several genes were differentially regulated by JQ1 treatment in Gnaq/11 mutant cells, with the downregulation of c-Myc, of the anti-apoptotic protein Bcl-2, and DNA repair proteins Rad51 and Brca1. While depletion of each of these genes did not affect cell viability, the concomitant silencing of Rad51 and Bcl-2 represented the minimal requirement to mimic the apoptotic effects of JQ1. As opposed to hematopoietic cancer cell lines, c-Myc depletion did not seem to play a major role in inhibiting the growth of these cells. Furthermore, the treatment with JQ1 resulted in significant antitumor activity in a mouse xenograft model of uveal melanoma with Gnaq mutation. Our results suggest the potential therapeutic use of BET bromodomain inhibitors for treating uveal melanoma with Gnaq/Gna11 mutations. Citation Format: Grazia Ambrosini. Differential effects of BRD4 inhibition on uveal melanoma cells with Gnaq/11 mutations. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B29.

  • abstract 1410 gnaq 11 mutant uveal melanoma is susceptible to brd4 inhibition by jq1
    2014
    Co-Authors: Grazia Ambrosini, Gary K Schwartz
    Abstract:

    Uveal melanoma (UM) represents the most common intraocular malignancy in the United States, and there are no effective treatments for this aggressive disease. Uveal melanoma is characterized by oncogenic mutations in Gnaq and Gna11, which activate the mitogen-activated protein kinase pathway (MAPK). Furthermore, both primary and metastatic UM are characterized by genetic abnormalities, including the amplification of the chromosomal arm 8q and monosomy of chromosome 3, which are significantly associated with poor prognosis. The Oncogene Myc, which is located on 8q24.1, is amplified in nearly 70% of uveal melanoma, and is also regulated by the MAPK pathway. Chromatin regulators have become attractive targets for cancer therapy. In particular, the BET-bromodomain inhibitor JQ1 has shown selective inhibition of c-Myc expression, followed by the suppression of c-Myc-dependent target genes. We examined the effects of JQ1 in a panel of 8 UM cell lines, including cell lines with Gnaq/Gna11 mutations (92.1, Omm1.3, Mel270, Mel202, Omm1), a cell line with Myc amplification (Mel290), and cells without either mutation or amplification (C918, Mel285). The Gnaq/Gna11 mutant cells were the most sensitive to growth inhibition at nanomolar concentrations of JQ1 (IC 50 =200nM), followed by the cell line with amplified Myc (IC 50 =1μM), while the cells without mutation or amplification exhibited little inhibition. We also examined the biochemical effects of JQ1 treatment, which caused a dose- and time-dependent suppression of c-Myc as well as survivin, XIAP, ERK1 and E2F1, while p21and the pro-apoptotic protein Bim were induced in all the cell lines. Interestingly, JQ1 also suppressed the anti-apoptotic protein Bcl-xL and induced PARP cleavage only in the Gnaq/Gna11 mutant cells. Flow cytometric analysis indicated a cell cycle arrest in G1 in all the cell lines and an apoptotic population in sub-G1in the mutant cells. Furthermore, treatment with JQ1 resulted in significant antitumor activity in mouse xenograft models of uveal melanoma with Gnaq mutation. All together, these observations support the evidence that JQ1 represent a promising therapeutic approach for uveal melanoma with Gnaq/Gna11 mutations. Citation Format: Grazia Ambrosini, Gary K. Schwartz. Gnaq/11 mutant uveal melanoma is susceptible to Brd4 inhibition by JQ1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1410. doi:10.1158/1538-7445.AM2014-1410

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