c-Myc-deficient B lymphocytes are resistant to spontaneous and induced cell death

Alborán, Ignacio Moreno de; Baena, Esther; Martı́nez-A, Carlos

doi:10.1038/sj.cdd.4401319

Cited by 28 publications

(28 citation statements)

References 35 publications

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“…c-Myc-deficient B lymphocytes show severely impaired cell proliferation as well as apoptosis resistance (26,27). We observed consistent lack of proliferation in c-Myc-deficient B lymphocytes after in vitro stimulation with anti-CD40 plus IL-4 (Supplemental Fig.…”

Section: Discussionsupporting

confidence: 56%

“…Transgenic mice that overexpress c-myc in B lymphocytes show abnormal B cell differentiation and rapid lymphoma development, leading ultimately to death (25). Mature B lymphocytes that lack c-Myc in vivo show severely impaired proliferation and resistance to apoptosis (26,27). Involvement of c-Myc in differentiation has been described for several cell types, including myeloid cells and B lymphocytes (18,(28)(29)(30).…”

mentioning

confidence: 99%

“…Our results provide unexpected insights into c-Myc function in terminal B cell differentiation, and they show the importance of this transcription factor as a key effector of the humoral response. ;rosa26 gfp/gfp ) mice has been reported (26,27).…”

mentioning

confidence: 99%

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The Proto-Oncogene c-myc Regulates 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: 56%

mentioning

confidence: 99%

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

Fernandez

Ortiz

Rodríguez

et al. 2013

The Journal of Immunology

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“…43,44 In the immune compartment, c-MYC is known to play a role in the control of lymphocyte homeostasis and survival/apoptosis of myeloid cells. 26,27 In the present study, we report that this transcription factor is induced in human macrophages during alternative activation and controls a significant fraction of genes associated with alternative activation, either through direct gene induction or via its weak effect on other known IL-4 key transcription factors.…”

Section: Discussionmentioning

confidence: 97%

“…25 More recently, a key role of this transcription factor in hematopoietic stem-cell function and survival and in lymphoid compartment homeostasis has also been reported. [26][27][28][29] In the present study, we report that c-MYC is induced in human macrophages activated by IL-4-and M2-like stimuli, and provide evidence for its involvement in the induction of a large set of genes during alternative macrophage activation, either by direct interaction or indirectly through induction of signal transducer and activator of transcription-6 (STAT6) and PPAR␥. We also report that c-MYC is expressed in TAMs, where it controls the expression of protumoral genes.…”

Section: Introductionmentioning

confidence: 92%

Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology

Pello¹,

Pizzol²,

Mirolo³

et al. 2012

Blood

296

254

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In response to microenvironmental signals, macrophages undergo different activation, including the "classic" proinflammatory phenotype (also called M1), the "alternative" activation induced by the IL-4/IL-13 trigger, and the related but distinct heterogeneous M2 polarization associated with the anti-inflammatory profile. The latter is induced by several stimuli, including IL-10 and TGF-␤. Macrophagepolarized activation has profound effects on immune and inflammatory responses and in tumor biology, but information on the underlying molecular pathways is scarce. In the present study, we report that alternative polarization of macrophages requires the transcription factor c-MYC. In macrophages, IL-4 and different stimuli sustaining M2-like polarization induce c-MYC expression and its translocation to the nucleus. c-MYC controls the induction of a subset (45%) of genes associated with alternative activation. ChIP assays indicate that c-MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptor␥, is also expressed in tumorassociated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1␣, and TGF-␤. We conclude that c-MYC is a key player in alternative macrophage activation, and is therefore a potential therapeutic target in pathologies related to these cells, including tumors. (Blood. 2012;119(2):411-421) IntroductionMacrophages are specialized phagocytic cells involved in multiple processes, both in homeostatic conditions and during the immune response after tissue damage or exposure to a pathogen. Macrophages are characterized by a striking heterogeneity, which can be partially ascribed to their origin by self-renewal of resident postmitotic cells and by monocyte subsets recruited and differentiated locally. 1-3 A second element shaping macrophage heterogeneity is the microenvironment, both under homeostatic conditions, with the hosting tissue profoundly influencing macrophage differentiation, and in the context of an inflammatory or immune response, which generates a wide range of polarized activation states. [3][4][5][6] Activation with IFN-␥, alone or in combination with pathogen-derived signals such as lipopolysaccharide (LPS), leads to classically activated macrophages, also referred to as M1 cells, which develop proinflammatory type 1 immune responses. Macrophage exposure to other immune signals results in profoundly different functional phenotypes. These include "alternatively activated" macrophages caused by IL-4/IL-13 stimulation, which are associated with type 2 immune responses and a spectrum of functional phenotypes related to anti-inflammatory, angiogenic, and tissue-repair properties induced in macrophages by stimuli including TGF-␤, immune complexes, glucocorticoids, and IL-10. 3,4,6,7 Further...

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Absence of sclerostin adversely affects B-cell survival

Cain

Rueda

McLelland

et al. 2012

Journal of Bone and Mineral Research

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Increased osteoblast activity in sclerostin‐knockout (Sost−/−) mice results in generalized hyperostosis and bones with small bone marrow cavities resulting from hyperactive mineralizing osteoblast populations. Hematopoietic cell fate decisions are dependent on their local microenvironment, which contains osteoblast and stromal cell populations that support both hematopoietic stem cell quiescence and facilitate B‐cell development. In this study, we investigated whether high bone mass environments affect B‐cell development via the utilization of Sost−/− mice, a model of sclerosteosis. We found the bone marrow of Sost−/− mice to be specifically depleted of B cells because of elevated apoptosis at all B‐cell developmental stages. In contrast, B‐cell function in the spleen was normal. Sost expression analysis confirmed that Sost is primarily expressed in osteocytes and is not expressed in any hematopoietic lineage, which indicated that the B‐cell defects in Sost−/− mice are non‐cell autonomous, and this was confirmed by transplantation of wild‐type (WT) bone marrow into lethally irradiated Sost−/− recipients. WT→Sost−/− chimeras displayed a reduction in B cells, whereas reciprocal Sost−/−→WT chimeras did not, supporting the idea that the Sost−/− bone environment cannot fully support normal B‐cell development. Expression of the pre‐B‐cell growth stimulating factor, Cxcl12, was significantly lower in bone marrow stromal cells of Sost−/− mice, whereas the Wnt target genes Lef‐1 and Ccnd1 remained unchanged in B cells. Taken together, these results demonstrate a novel role for Sost in the regulation of bone marrow environments that support B cells. © 2012 American Society for Bone and Mineral Research.

show abstract

c-Myc-deficient B lymphocytes are resistant to spontaneous and induced cell death

Cited by 28 publications

References 35 publications

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

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

Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology

Absence of sclerostin adversely affects B-cell survival

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