Blimp-1 Orchestrates Plasma Cell Differentiation by Extinguishing the Mature B Cell Gene Expression Program
TL;DR: These findings suggest that Blimp-1 promotes plasmacytic differentiation by extinguishing gene expression important for B cell receptor signaling, germinal center B cell function, and proliferation while allowing expression of important plasma cell genes such as XBP-1.
About: This article is published in Immunity.The article was published on 2002-07-01 and is currently open access. It has received 1013 citations till now. The article focuses on the topics: Plasma cell differentiation & Cellular differentiation.
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TL;DR: It is found that expression of the transcription factor Bcl6 in CD4+ T cells is both necessary and sufficient for in vivo TFH differentiation and T cell help to B cells in mice, and that Bcl 6 and Blimp-1 play central but opposing roles inTFH differentiation.
Abstract: Effective B cell–mediated immunity and antibody responses often require help from CD4+ T cells. It is thought that a distinct CD4+ effector T cell subset, called T follicular helper cells (TFH), provides this help; however, the molecular requirements for TFH differentiation are unknown. We found that expression of the transcription factor Bcl6 in CD4+ T cells is both necessary and sufficient for in vivo TFH differentiation and T cell help to B cells in mice. In contrast, the transcription factor Blimp-1, an antagonist of Bcl6, inhibits TFH differentiation and help, thereby preventing B cell germinal center and antibody responses. These findings demonstrate that TFH cells are required for proper B cell responses in vivo and that Bcl6 and Blimp-1 play central but opposing roles in TFH differentiation.
1,400 citations
Broad Institute1, Mayo Clinic2, Harvard University3, Multiple Myeloma Research Foundation4, Translational Genomics Research Institute5, Howard Hughes Medical Institute6, Weizmann Institute of Science7, Ohio State University8, Catholic Medical Center9, University of Michigan10, City of Hope National Medical Center11, Emory University12, Rutgers University13, Washington University in St. Louis14, University of Chicago15, Massachusetts Institute of Technology16
TL;DR: The massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs indicates that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.
Abstract: Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.
1,323 citations
Broad Institute1, Mayo Clinic2, Harvard University3, Multiple Myeloma Research Foundation4, Translational Genomics Research Institute5, Howard Hughes Medical Institute6, Weizmann Institute of Science7, Ohio State University8, Catholic Medical Center9, University of Michigan10, City of Hope National Medical Center11, Emory University12, Rutgers University13, Washington University in St. Louis14, University of Chicago15, Massachusetts Institute of Technology16
TL;DR: In this paper, a massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs was reported, and several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set.
Abstract: Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.
1,134 citations
TL;DR: A population of Foxp3+Blimp-1+CD4+ T cells constituting 10–25% of the CXCR5highPD-1highCD4- T cells found in the germinal center after immunization with protein antigens are described.
Abstract: Follicular helper (T(FH)) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T(FH) numbers maintains self tolerance. We describe a population of Foxp3(+)Blimp-1(+)CD4(+) T cells constituting 10-25% of the CXCR5(high)PD-1(high)CD4(+) T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T(FR)) cells share phenotypic characteristics with T(FH) and conventional Foxp3(+) regulatory T (T(reg)) cells yet are distinct from both. Similar to T(FH) cells, T(FR) cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T(FR) cells originate from thymic-derived Foxp3(+) precursors, not naive or T(FH) cells. T(FR) cells are suppressive in vitro and limit T(FH) cell and germinal center B cell numbers in vivo. In the absence of T(FR) cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T(FH) differentiation pathway is co-opted by T(reg) cells to control the germinal center response.
1,019 citations
TL;DR: The regulation of antibody production is linked to the generation and maintenance of plasmablasts and plasma cells from their B cell precursors, and the terminal differentiation of B cells can be described as a simple probabilistic process governed by a central gene-regulatory network and modified by environmental stimuli.
Abstract: The regulation of antibody production is linked to the generation and maintenance of plasmablasts and plasma cells from their B cell precursors. Plasmablasts are the rapidly produced and short-lived effector cells of the early antibody response, whereas plasma cells are the long-lived mediators of lasting humoral immunity. An extraordinary number of control mechanisms, at both the cellular and molecular levels, underlie the regulation of this essential arm of the immune response. Despite this complexity, the terminal differentiation of B cells can be described as a simple probabilistic process that is governed by a central gene-regulatory network and modified by environmental stimuli.
1,005 citations
References
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TL;DR: A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression, finding in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function.
Abstract: A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is de- scribed that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be inter- preted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly charac- terized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.
16,371 citations
TL;DR: It is shown that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour.
Abstract: 12 Pathology and Microbiology, and 13 Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.
9,493 citations
"Blimp-1 Orchestrates Plasma Cell Di..." refers methods in this paper
...…of Blimp-1’s control over present in plasma cells formed in primary and secondary terminal B cell differentiation, we used DNA microarrays responses to T cell-dependent and -independent antigens (Alizadeh et al., 2000) to analyze gene expression changes caused by manipulation of Blimp-1 activity....
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TL;DR: Results suggest that AID may be involved in regulation or catalysis of the DNA modification step of both class switching and somatic hypermutation in CH12F3-2 B lymphoma.
3,288 citations
TL;DR: It is demonstrated that mutations in either ire-1 or the transcription-factor-encoding xbp-1 gene abolished the UPR in Caenorhabditis elegans, suggesting that physiological ER load regulates a developmental decision in higher eukaryotes.
Abstract: The unfolded protein response (UPR), caused by stress, matches the folding capacity of endoplasmic reticulum (ER) to the load of client proteins in the organelle. In yeast, processing of HAC1 mRNA by activated Ire1 leads to synthesis of the transcription factor Hac1 and activation of the UPR. The responses to activated IRE1 in metazoans are less well understood. Here we demonstrate that mutations in either ire-1 or the transcription-factor-encoding xbp-1 gene abolished the UPR in Caenorhabditis elegans. Mammalian XBP-1 is essential for immunoglobulin secretion and development of plasma cells, and high levels of XBP-1 messenger RNA are found in specialized secretory cells. Activation of the UPR causes IRE1-dependent splicing of a small intron from the XBP-1 mRNA both in C. elegans and mice. The protein encoded by the processed murine XBP-1 mRNA accumulated during the UPR, whereas the protein encoded by unprocessed mRNA did not. Purified mouse IRE1 accurately cleaved XBP-1 mRNA in vitro, indicating that XBP-1 mRNA is a direct target of IRE1 endonucleolytic activity. Our findings suggest that physiological ER load regulates a developmental decision in higher eukaryotes.
2,643 citations
TL;DR: The c-myc gene was discovered as the cellular homolog of the retroviral v- myc oncogene 20 years ago and found to be activated in various animal and human tumors, suggesting that it is critical for development.
Abstract: The c-myc gene was discovered as the cellular homolog of the retroviral v-myc oncogene 20 years ago (23, 25, 167). The c-myc proto-oncogene was subsequently found to be activated in various animal and human tumors (37, 39, 42). It belongs to the family of myc genes that includes B-myc, L-myc, N-myc, and s-myc; however, only c-myc, L-myc, and N-myc have neoplastic potential (54, 82, 102, 118, 178). Targeted homozygous deletion of the murine c-myc gene results in embryonic lethality, suggesting that it is critical for development (43). Homozygous inactivation of c-myc in rat fibroblasts caused a marked prolongation of cell doubling time, further suggesting a central role for c-myc in regulating cell proliferation (121).
The frequency of genetic alterations of c-myc in human cancers (42) has allowed an estimation that approximately 70,000 U.S. cancer deaths per year are associated with changes in the c-myc gene or its expression. Given that c-myc may contribute to one-seventh of U.S. cancer deaths, recent efforts have been directed toward understanding the function of the c-Myc protein in cancer biology with the hope that therapeutic insights will emerge. Past efforts, which have contributed significantly to our current understanding of c-myc, are discussed in a number of excellent reviews (23, 29, 37, 40, 44, 52, 66, 82, 94, 102, 118, 125, 132, 145, 178, 182, 186).
1,630 citations