Targeted Overexpression of the Transcription Factor XBP-1 in B Cells Promotes Plasma Cell and Lymphoplasmacytic Neoplasms in Transgenic Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 359-359 ◽  
Author(s):  
Ruben D. Carrasco ◽  
Kumar Sukhdeo ◽  
Marina Protopopova ◽  
Masha German ◽  
Joel Henderson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
Growth Factor ◽  
B Cell ◽  
Signaling Pathways ◽  
Plasma Cell ◽  
Rna Processing ◽  
Cell Lineage ◽  
Growth Factor Signaling ◽  
Factor X

Abstract The transcription factor X-box binding protein-1 (XBP-1) plays critical roles in the unfolded protein response (UPR), the differentiation of plasma cells, and the regulation of growth factor signaling pathways. XBP-1 is subject to regulation by alternative RNA processing producing XBP-1-spliced (S) and -unspliced (U) mRNAs encoding proteins with identical DNA-binding and bZIP domains yet distinct C-terminal transactivation domains. The weaker transactivation potential of XBP-1(U) has prompted speculation that it may influence XBP-1(S) activity as a transdominant mutant. While elevated XBP-1 expression has been reported in transformed cells, the relative ratios of these XBP-1 isoforms and associated physiological relevance in cancer are uncertain. Here, we assessed the differential impact of enforced XBP-1(S) versus XBP-1(U) transgene expression in the B cell lineage. Both transgenes elicited early onset antibody-dependent autoimmune disease characterized by elevated levels of serum immunoglobulin (Ig) and IL-6 production, increased numbers of marginal zone and mature follicular B cells in the spleen, and expanded mature B cell populations in the bone marrow. Notably, aged XBP-1(S) mice developed clonal plasma cell expansions, culminating in the human-equivalent of Monoclonal Gammopathy of Undetermined Significance (MGUS) or Multiple Myeloma (MM). Conversely, XBP-1(U) mice develop multi-organ lymphoplasmacytic infiltrates and, with advancing age, succumb to neoplasms resembling human Lymphoplasmacytic Lymphoma/Waldenstrom’s Macroglobulinemia (LPL/WM). These unanticipated genetic observations in the mouse were translated to human disease with documentation of elevated levels of XBP-1(S) in MM and XBP-1(U) in LPL/WM. Together, these results indicate that imbalances in XBP-1(S) and XBP-1(U) alters B cell lineage homeostasis and can drive two distinct types of lymphoplasmacytic neoplasms in vivo. The findings of this study, together with the known capacity of XBP-1 to regulate various cancer-relevant growth factor signaling pathways, predicts that epigenetic dysregulation of alternate XBP-1 RNA processing can promote age-associated B cell malignancies in humans.

scholarly journals YY1 plays an essential role at all stages of B-cell differentiation

2016 ◽  
Vol 113 (27) ◽  
pp. E3911-E3920 ◽  
Author(s):  
Eden Kleiman ◽  
Haiqun Jia ◽  
Salvatore Loguercio ◽  
Andrew I. Su ◽  
Ann J. Feeney
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Signaling Pathways ◽  
Mrna Splicing ◽  
Cell Populations ◽  
Sequencing Analysis ◽  
B Cell Differentiation ◽  
Chip Sequencing

Ying Yang 1 (YY1) is a ubiquitously expressed transcription factor shown to be essential for pro–B-cell development. However, the role of YY1 in other B-cell populations has never been investigated. Recent bioinformatics analysis data have implicated YY1 in the germinal center (GC) B-cell transcriptional program. In accord with this prediction, we demonstrated that deletion of YY1 by Cγ1-Cre completely prevented differentiation of GC B cells and plasma cells. To determine if YY1 was also required for the differentiation of other B-cell populations, we deleted YY1 with CD19-Cre and found that all peripheral B-cell subsets, including B1 B cells, require YY1 for their differentiation. Transitional 1 (T1) B cells were the most dependent upon YY1, being sensitive to even a half-dosage of YY1 and also to short-term YY1 deletion by tamoxifen-induced Cre. We show that YY1 exerts its effects, in part, by promoting B-cell survival and proliferation. ChIP-sequencing shows that YY1 predominantly binds to promoters, and pathway analysis of the genes that bind YY1 show enrichment in ribosomal functions, mitochondrial functions such as bioenergetics, and functions related to transcription such as mRNA splicing. By RNA-sequencing analysis of differentially expressed genes, we demonstrated that YY1 normally activates genes involved in mitochondrial bioenergetics, whereas it normally down-regulates genes involved in transcription, mRNA splicing, NF-κB signaling pathways, the AP-1 transcription factor network, chromatin remodeling, cytokine signaling pathways, cell adhesion, and cell proliferation. Our results show the crucial role that YY1 plays in regulating broad general processes throughout all stages of B-cell differentiation.

scholarly journals The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity

2014 ◽  
Vol 211 (5) ◽  
pp. 827-840 ◽  
Author(s):  
Stéphane Chevrier ◽  
Dianne Emslie ◽  
Wei Shi ◽  
Tobias Kratina ◽  
Cameron Wellard ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Cycle Progression ◽  
Plasma Cells ◽  
Cell Lineage ◽  
B Cell Differentiation ◽  
Antibody Secreting Cell ◽  
Important Player

The transcriptional network regulating antibody-secreting cell (ASC) differentiation has been extensively studied, but our current understanding is limited. The mechanisms of action of known “master” regulators are still unclear, while the participation of new factors is being revealed. Here, we identify Zbtb20, a Bcl6 homologue, as a novel regulator of late B cell development. Within the B cell lineage, Zbtb20 is specifically expressed in B1 and germinal center B cells and peaks in long-lived bone marrow (BM) ASCs. Unlike Bcl6, an inhibitor of ASC differentiation, ectopic Zbtb20 expression in primary B cells facilitates terminal B cell differentiation to ASCs. In plasma cell lines, Zbtb20 induces cell survival and blocks cell cycle progression. Immunized Zbtb20-deficient mice exhibit curtailed humoral responses and accelerated loss of antigen-specific plasma cells, specifically from the BM pool. Strikingly, Zbtb20 induction does not require Blimp1 but depends directly on Irf4, acting at a newly identified Zbtb20 promoter in ASCs. These results identify Zbtb20 as an important player in late B cell differentiation and provide new insights into this complex process.

Differential Expression and Non-Redundant Functions of NF-κB Transcription Factor Subunits in Germinal Center (GC) B Cell Subpopulations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 216-216 ◽  
Author(s):  
Nicole Heise ◽  
Nilushi De Silva ◽  
Amanda Carette ◽  
Giorgia Simonetti ◽  
Govind Bhagat ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Differential Expression ◽  
Plasma Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Nuclear Translocation ◽  
Cell Subpopulations

Abstract Abstract 216 The majority of B cell-derived neoplasms, including Hodgkin and Non-Hodgkin lymphoma and multiple myeloma (MM), arise from antigen-specific B cells that have undergone the germinal center (GC) reaction of T-dependent immune responses. Recent work has demonstrated that GC-derived tumors frequently harbor genetic mutations in nuclear factor-κB (NF-κB) signaling pathway components, resulting in the constitutive activation of NF-κB signaling, thus identifying NF-κB as a critical player in GC-lymphomagenesis. Moreover, there is evidence for a preferential activation of particular NF-κB transcription factor subunits in tumor subtypes. Despite extensive knowledge about the biology of NF-κB, its potential function in the physiology and development of GC B cells, the presumptive tumor precursor cells, is largely unresolved. The NF-κB signaling cascade comprises 5 different subunits, which occur as homo- and heterodimers and can be activated via two different routes, the canonical (classical) and the alternative (non-canonical/classical) NF-κB pathways. RELA, c-REL and p105/p50 represent the subunits of the canonical, while RELB and p100/p52 comprise those of the alternative pathway. It is known that there is no active NF-κB signaling in tonsillar GC centroblasts. Conversely, NF-κB activation was shown to occur in a subset of GC centrocytes. In this study, we demonstrate that each of the 5 NF-κB subunits exhibit nuclear translocation in centrocytes. Surprisingly, we observed that centrocytes expressing the plasma cell master regulator BLIMP1 showed strong immunofluorescence (IF) staining for the alternative NF-κB subunit p100/p52 and weak expression of the canonical subunits p105/p50 and c-REL compared to surrounding lymphocytes. Plasma cells localized in the tonsillar subepithelium showed the same pattern of expression. This observed differential expression of alternative vs. canonical NF-κB subunits in plasma cells and B cells, respectively, is supported by gene expression profiling data of human B cell subpopulations. Moreover, we observed that a mouse lymphoma cell line (M12) shows activation of the alternative NF-κB pathway upon induction of plasma cell differentiation. Also, Western and IF analysis of MM vs. diffuse large B cell lymphoma (DLBCL) cell lines revealed high protein levels and nuclear translocation of both p52 and RELB and low levels and cytosolic localization of c-REL in MM cell lines, while the opposite pattern was observed in the analyzed DLBCL lines. In summary, the elevated protein expression and presumed activity of the alternative over the canonical NF-κB pathway in plasma cells and their precursors suggests that activation of the alternative NF-κB pathway in centrocytes may contribute to plasma cell development and/or physiology. To elucidate the in vivo function of individual NF-κB transcription factor subunits, we started by determining the extent to which deletion of c-REL specifically in GC B cells affects the biology and differentiation of GC and post-GC B cells. We generated and then crossed a conditional loxP-flanked rel (c-REL) allele to mice that express the Cre-recombinase in GC B cells instructed to undergo class switch recombination (Cγ1-Cre mice). Following immunization with a T-dependent antigen, PNA+CD95+ GC B cell numbers were markedly reduced in immunized relfl/flCγ1-Cre mice compared to rel+/+Cγ1-Cre control mice. In addition, immunohistochemical analysis of spleen sections for BCL6 and IgG1 showed significantly smaller GCs, and a strong reduction in the numbers of GC-derived IgG1-secreting plasma cells, in relfl/flCγ1-Cre mice compared to controls. Consistent with these findings, we observed that relfl/flCγ1-Cre mice showed dramatically reduced numbers of nitrophenyl (NP) hapten-specific cells 14 days after immunization with NP-KLH compared to the control mice. Taken together, these findings suggest that c-REL may be required for the maintenance of GC B cells or for their selection into the post-GC compartment. Of note, the results demonstrate that deletion of a single NF-κB subunit in GC B cells can have drastic effects, suggesting a lack of general redundancy of the canonical subunits during the GC reaction. These findings imply that c-REL activation needs to be tightly controlled during GC B cell development, and raise the possibility that other NF-κB subunits may also exert unique functions in GC B cell differentiation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Active Inhibition of Plasma Cell Development in Resting B Cells by Microphthalmia-associated Transcription Factor

2004 ◽  
Vol 200 (1) ◽  
pp. 115-122 ◽  
Author(s):  
Ling Lin ◽  
Andrea J. Gerth ◽  
Stanford L. Peng
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Activation ◽  
Terminal Differentiation ◽  
B Cell Activation ◽  
Autoantibody Production ◽  
B Cell Homeostasis ◽  
Antibody Secretion

B cell terminal differentiation involves development into an antibody-secreting plasma cell, reflecting the concerted activation of proplasma cell transcriptional regulators, such as Blimp-1, IRF-4, and Xbp-1. Here, we show that the microphthalmia-associated transcription factor (Mitf) is highly expressed in naive B cells, where it antagonizes the process of terminal differentiation through the repression of IRF-4. Defective Mitf activity results in spontaneous B cell activation, antibody secretion, and autoantibody production. Conversely, ectopic Mitf expression suppresses the expression of IRF-4, the plasma cell marker CD138, and antibody secretion. Thus, Mitf regulates B cell homeostasis by suppressing the antibody-secreting fate.

scholarly journals Deletion of genes encoding PU.1 and Spi-B in B cells impairs differentiation and induces pre-B cell acute lymphoblastic leukemia

Blood ◽  
2011 ◽  
Vol 118 (10) ◽  
pp. 2801-2808 ◽  
Author(s):  
Kristen M. Sokalski ◽  
Stephen K. H. Li ◽  
Ian Welch ◽  
Heather-Anne T. Cadieux-Pitre ◽  
Marek R. Gruca ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Acute Lymphoblastic Leukemia ◽  
B Cells ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
B Cell Differentiation ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Ets Transcription Factor

Abstract The E26 transformation-specific (Ets) transcription factor PU.1 is required to generate lymphoid progenitor cells from hematopoietic stem cells, but it is not required to generate B cells from committed B-cell lineage progenitors. We hypothesized that PU.1 function in B-cell differentiation is complemented by the related Ets transcription factor Spi-B. To test this hypothesis, mice were generated lacking both PU.1 and Spi-B in the B-cell lineage. Unlike mice lacking PU.1 or Spi-B, mice deficient in both PU.1 and Spi-B in the B-cell lineage had reduced frequencies of B cells as well as impaired B-cell differentiation. Strikingly, all PU.1 and Spi-B–deficient mice developed pre-B cell acute lymphoblastic leukemia before 30 weeks of age. Pre-B cells accumulated in the thymus resulting in massive thymic enlargement and dyspnea. These findings demonstrate that PU.1 and Spi-B are essential transcriptional regulators of B-cell differentiation as well as novel tumor suppressors in the B-cell lineage.

scholarly journals Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5857-5867 ◽  
Author(s):  
Teresita L. Arenzana ◽  
Matthew R. Smith-Raska ◽  
Boris Reizis
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Lineage ◽  
Cell Development ◽  
B Cell Development ◽  
Stem Cell Maintenance ◽  
And Function ◽  
Cell Maintenance

Abstract The development, homeostasis, and function of B lymphocytes involve multiple rounds of B-cell receptor (BCR)–controlled proliferation and prolonged maintenance. We analyzed the role of transcription factor Zfx, a recently identified regulator of hematopoietic stem cell maintenance, in B-cell development and homeostasis. Panhematopoietic or B cell–specific deletion of Zfx in the bone marrow blocked B-cell development at the pre-BCR selection checkpoint. Zfx deficiency in peripheral B cells caused accelerated B-cell turnover, depletion of mature recirculating B cells, and delayed T-dependent antibody responses. In addition, the numbers and function of B-1 cell lineage were reduced. Zfx-deficient B cells showed normal proximal BCR signaling, but impaired BCR-induced proliferation and survival in vitro. This was accompanied by aberrantly enhanced and prolonged integrated stress response and by delayed induction of cyclin D2 and Bcl-xL proteins. Thus, Zfx restrains the stress response and couples antigen receptor signaling to cell expansion and maintenance during B-cell development and peripheral homeostasis. These results identify a novel transcriptional regulator of the B-cell lineage and highlight the common genetic control of stem cell maintenance and lymphocyte homeostasis.

Commitment and differentiation of lung cell lineages

1998 ◽  
Vol 76 (6) ◽  
pp. 971-995 ◽  
Author(s):  
David Warburton ◽  
Carol Wuenschell ◽  
Guillermo Flores-Delgado ◽  
Kathryn Anderson
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Cell Lineage ◽  
Branching Morphogenesis ◽  
Growth Factor Signaling ◽  
Cell Lineages ◽  
Master Genes ◽  
Lung Morphogenesis ◽  
Peptide Growth Factor

To form a large diffusible interface capable of conducting respiratory gases to and from the circulation, the lung must undergo extensive cell proliferation, branching morphogenesis, and alveolar saccule formation, to generate sufficient surface area. In addition, the cells must differentiate into at least 40 distinct lung cell lineages. Specific transcriptional factors, peptide growth factor receptor-mediated signaling pathways, extracelluar matrix components, and integrin-signaling pathways interact to direct lung morphogenesis and lung cell lineage differentiation. Branching mutants of the respiratory tracheae in Drosophila have identified several functionally conserved genes in the fibroblast growth factor signaling pathway that also regulate pulmonary organogenesis in mice and probably also in man. Key transcriptional factors including Nkx2.1, hepatocyte nuclear factor family forkhead homologues, GATA family zinc finger factors, pou and homeodomain proteins, as well as basic helix-loop-helix factors, serve as master genes to integrate the developmental genetic instruction of lung morphogenesis and cell lineage determination. Key words: lung branching morphogenesis, lung cell proliferation, lung cell differentiation, alveolization, master genes, peptide growth factor signaling, extracellular matrix signaling, mesenchyme induction, alveolar epithelial cells, pulmonary neuroendocrine cells, stem cells, retinoic acid.

scholarly journals Single-cell analysis of developing B cells reveals dynamic gene expression networks that govern B cell development and transformation

2020 ◽  
Author(s):  
Robin D. Lee ◽  
Sarah A. Munro ◽  
Todd P. Knutson ◽  
Rebecca S. LaRue ◽  
Lynn M. Heltemes-Harris ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Single Cell ◽  
Rna Binding ◽  
Single Cell Analysis ◽  
Cell Transformation ◽  
Cell Lineage ◽  
Cell Development ◽  
B Cell Development

SummaryIntegration of external signals and B-lymphoid transcription factor activities orchestrate B cell lineage commitment through alternating cycles of proliferation and differentiation, producing a diverse repertoire of mature B cells. We used single-cell transcriptomics and proteomics to characterize B cell development. Our analysis revealed unique transcriptional signatures that refine the pre-B cell expansion stages into novel pre-BCR-dependent and pre-BCR-independent proliferative phases. These changes correlate with unexpected dynamic and reciprocal changes in expression of the transcription factor EBF1 and the RNA binding protein YBX3, that are defining features of the pre-BCR-dependent stage. Using pseudotime analysis, we further characterize the expression kinetics of different biological modalities across B cell development, including transcription factors, cytokines, chemokines, and their associated receptors. Our findings reveal the underlying heterogeneity of developing B cells and point to key developmental nodes linked to B cell transformation.

The IL-7 Receptor alpha Promoter Is Activated at Distinct Stages during B Cell Development by the Ets Transcription Factors PU.1 and GABP.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3157-3157
Author(s):  
Rodney P. DeKoter ◽  
Brock L. Schweitzer ◽  
Darrel Jones ◽  
David A. Hildeman ◽  
Kelly J. Huang
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Binding Site ◽  
Progenitor Cells ◽  
Promoter Activity ◽  
Cell Lineage ◽  
Cell Development ◽  
B Cell Development ◽  
Lymphocyte Development

Abstract The cytokine interleukin-7 (IL-7) is required for B and T lymphocyte development, and for the survival and maintenance of both naive and memory T lymphocytes. The receptor for IL-7 (IL-7R) is heterodimeric, consisting of a common gamma chain (γc) and an alpha subunit (IL-7Rα). The γc is expressed in most hematopoietic cell types, but the IL-7Rα gene is regulated in a cell type and developmental stage-specific manner. We have previously shown that the Ets-family transcription factor PU.1 is required to activate transcription of the IL-7Rα gene during fetal lymphocyte development. However, several questions remain unanswered. First, the IL-7Rα promoter is poorly characterized. Second, the IL-7Rα is expressed at high levels in the T cell lineage where PU.1 is not expressed. Third, the transcription factor early B cell factor (EBF) can activate IL-7Rα transcription in developing B cells in the absence of PU.1. To address these questions, we have characterized the IL-7Rα promoter region in detail. First, we determined that the major transcription start sites in the IL-7Rα gene are downstream of an Ets/PU.1 binding site. We found that the intact Ets site is required for IL-7Rα promoter activity, as well as to mediate enhancer action from a distance. IL-7Rα promoter activity depends on the proper orientation of the Ets site relative to functional initiator sequences. We found, using gel shift analysis, that both PU.1 and the Ets transcription factor GA binding protein (GABP) are expressed in developing B cells, and can interact with the Ets binding site in the IL-7Rα promoter. However, the function of PU.1 is distinct from GABP during B cell development. Retroviral transduction of PU.1 mutant progenitor cells with a PU.1 retrovirus robustly rescues IL-7Rα transcription and IL-7-dependent B cell development. In contrast, transduction with GABPα and GABPβ1 subunits fails to activate IL-7Rα transcription in PU.1 mutant progenitor cells. We conclude that activation of the IL-7Rα gene requires PU.1 during the earliest stages of lymphocyte development, but is alternatively utilized by PU.1 and GABP after commitment to the B cell lineage.

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