The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry

Dominguez-Sola, David; Victora, Gabriel D.; Ying, Carol Y.; Phan, Ryan T.; Saito, Masumichi; Nussenzweig, Michel C.; Dalla‐Favera, Riccardo

doi:10.1038/ni.2428

Cited by 428 publications

(567 citation statements)

References 58 publications

(135 reference statements)

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“…c-Myc-deficient B lymphocytes have a severe impairment in the generation of B220 lo syndecan-1 + cells in response to immunization with either TNP-KLH or LPS. These results correlated with the pattern of expression of c-myc during the formation of GC as shown by Dominguez-Sola et al (51).…”

Section: Discussionsupporting

confidence: 87%

The Proto-Oncogene c-mycRegulates Antibody Secretion and Ig Class Switch Recombination

Fernandez

Ortiz

Rodríguez

et al. 2013

The Journal of Immunology

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The immune response involves the generation of Ab-secreting cells and memory B cells through a process called terminal B lymphocyte differentiation. This program requires the transcriptional repressor Blimp-1, which inhibits c-myc expression and terminates proliferation. Although the role of c-Myc in cell proliferation is well characterized, it is not known whether it has other functions in terminal differentiation. In this study, we show that c-Myc not only regulates cell proliferation, but it is also essential for Ab-secreting cell function and differentiation in vivo. c-Myc–deficient B lymphocytes hypersecrete IgM and do not undergo Ig class switch recombination (CSR). CSR has been previously linked to proliferation, and in this study we mechanistically link class switching and proliferation via c-Myc. We observed that c-Myc regulates CSR by transcriptionally activating the B cell–specific factor activation-induced cytidine deaminase. By linking cell proliferation and CSR, c-Myc is thus a critical component for a potent immune response

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Section: Discussionsupporting

confidence: 87%

The Proto-Oncogene c-mycRegulates Antibody Secretion and Ig Class Switch Recombination

Fernandez

Ortiz

Rodríguez

et al. 2013

The Journal of Immunology

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“…PAX5 activates the expression of Bach2 in B cells, which in turn represses Blimp1 expression, thus preventing premature exit from the GC reaction and differentiation into plasma cells (8)(9)(10). Loss of other factors including Oct2/Obf1, Batf, Myc, and SpiB also have both been shown to severely diminish GC formation, although in most cases the exact mechanisms remain to be fully determined (11)(12)(13)(14)(15)(16).…”

Section: Cd4 + T Cells Follicular Dendritic Cells and Macrophagesmentioning

confidence: 99%

“…To address this, Irf4 fl/+ CD23-Cre mice and Irf4 fl/2 CD23-Cre mice were immunized with NP-KLH, and the formation of early GC B cells was examined 5 d later, a time point when early GC B cells can first be detected in wildtype mice, yet the GC-structure with the characteristic dark and light zone is not present (11,12,42). In these experiments, we compared Irf4 fl/2 CD23-Cre (null) and control Irf4 fl/+ CD23-Cre (heterozygous) B cells because this allowed the unambiguous identification of IRF4-deficient B cells using eGFP and revealed that the extent of IRF4 deletion in the NP-reactive B cells was comparable between the genotypes (Supplemental Fig.…”

Section: Irf4 Is Required For the Generation Of Early Gc B Cellsmentioning

confidence: 99%

Transcription Factor IRF4 Regulates Germinal Center Cell Formation through a B Cell–Intrinsic Mechanism

Willis

Good-Jacobson

Curtis

et al. 2014

The Journal of Immunology

110

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In response to antigenic stimulation, mature B cells interact with follicular helper T cells in specialized structures called germinal centers (GCs), which leads to the development of memory B cells and Ab-secreting plasma cells. The transcription factor IFN regulatory factor 4 (IRF4) is essential for the formation of follicular helper T cells and thus GCs, although whether IRF4 plays a distinct role in GC B cells remains contentious. RNAseq analysis on ex vivo-derived mouse B cell populations showed that Irf4 was lowly expressed in naive B cells, highly expressed in plasma cells, but absent from GC B cells. In this study, we used conditional deletion of Irf4 in mature B cells as well as wild-type and Irf4-deficient mixed bone marrow chimeric mice to investigate how and where IRF4 plays its essential role in GC formation. Strikingly, GC formation was severely impaired in mice in which Irf4 was conditionally deleted in mature B cells, after immunization with protein Ags or infection with Leishmania major. This effect was evident as early as day 5 following immunization, before the development of GCs, indicating that Irf4 was required for the development of early GC B cells. This defect was B cell intrinsic because Irf4-deficient B cells in chimeric mice failed to participate in the GC in response to L. major or influenza virus infection. Taken together, these data demonstrate a B cell–intrinsic requirement for IRF4 for not only the development of Ab secreting plasma cells but also for GC formation.

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“…MYC is known to directly induce the expression of the prooncogenic miR-17-92 cluster (3), but it is also involved in a widespread down-regulation of miRNA expression (35). In the specific context of the GC reaction, it is important to note that MYC is not expressed in most B cells because its transcription is directly repressed by BCL6 (36). Thus, the expression of miR-28 in normal GC B cells is consistent with the absence of MYC in the same cells, whereas the ectopic, deregulated MYC expression in BL is consistent with miR-28 repression in these tumor cells.…”

Section: Mir-28 As a Candidate Tumor Suppressor In Gc-derived Lymphomasmentioning

confidence: 99%

microRNA 28 controls cell proliferation and is down-regulated in B-cell lymphomas

Schneider

Setty

Holmes

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma (B-NHL), which originates from germinal center (GC) B cells and harbors translocations deregulating v-myc avian myelocytomatosis viral oncogene homolog (MYC). A comparative analysis of microRNAs expressed in normal and malignant GC B cells identified microRNA 28 (miR-28) as significantly down-regulated in BL, as well as in other GC-derived B-NHL. We show that reexpression of miR-28 impairs cell proliferation and clonogenic properties of BL cells by modulating several targets including MAD2 mitotic arrest deficientlike 1, MAD2L1, a component of the spindle checkpoint whose downregulation is essential in mediating miR-28-induced proliferation arrest, and BCL2-associated athanogene, BAG1, an activator of the ERK pathway. We identify the oncogene MYC as a negative regulator of miR-28 expression, suggesting that its deregulation by chromosomal translocation in BL leads to miR-28 suppression. In addition, we show that miR-28 can inhibit MYC-induced transformation by directly targeting genes up-regulated by MYC. Overall, our data suggest that miR-28 acts as a tumor suppressor in BL and that its repression by MYC contributes to B-cell lymphomagenesis.

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The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry

Cited by 428 publications

References 58 publications

The Proto-Oncogene c-mycRegulates Antibody Secretion and Ig Class Switch Recombination

The Proto-Oncogene c-mycRegulates Antibody Secretion and Ig Class Switch Recombination

Transcription Factor IRF4 Regulates Germinal Center Cell Formation through a B Cell–Intrinsic Mechanism

microRNA 28 controls cell proliferation and is down-regulated in B-cell lymphomas

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