Down-regulation of murine B lymphocyte growth: arrest of B cells in G1 underlies immunosuppression induced by an IgM antibody

1992 ◽  
Vol 33 (3) ◽  
pp. 255-261 ◽  
Author(s):  
Ferenc Uher ◽  
Rudolf Mihalik ◽  
Maria E. Alonso ◽  
János Gergely
Keyword(s):  
B Cells ◽  
B Lymphocyte ◽  
Growth Arrest ◽  
Down Regulation ◽  
Igm Antibody ◽  
Lymphocyte Growth

Microarray Analysis of PU.1-Induced Growth Arrest and Apoptosis of Myeloma Cell Lines.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2499-2499
Author(s):  
Shikiko Ueno ◽  
Hiro Tatetsu ◽  
Naoko Harada ◽  
Hiroyuki Hata ◽  
Tadafumi Iino ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cell Growth ◽  
Cell Lines ◽  
Growth Arrest ◽  
Myeloma Cell ◽  
Down Regulation ◽  
Cell Growth Arrest ◽  
Myeloma Cells ◽  
Enhancer Region

Abstract PU.1 is an Ets family transcription factor, which is important for differentiation of granulocytes, monocytes/macrophages, and B cells. In the Friend leukemia model, it is reported that the failure of PU.1 down-regulation in erythroblasts reportedly results in differentiation arrest that leads to erythroleukemia. In conditional knockout mice of the 3.5 kb length of enhancer region located in14 kb 5′ of the PU.1 gene, PU.1 is down-regulated in myeloid cells and B cells down to 20% of that of wild type, and such mice develop acute myeloid leukemia and CLL-like disease. In addition, a deletion of the 3.5 kb enhancer region, which also contains the suppressor region for PU.1 in T cells, results in ectopic expression of PU.1 in T cells, which leads to T cell lymphoma in those mice. Taken together, the failure of up-regulation or down-regulation of PU.1 in certain differentiation stages for each lineage appears to cause differentiation arrest and hematological malignancies. We recently reported that PU.1 is down-regulated in a majority of myeloma cell lines through the methylation of the promoter and enhancer region located in17 kb 5′ of human PU.1 gene which is homologous to that in14 kb 5′ of murine PU.1 gene. Conditionally expressed PU.1 induced cell growth arrest and apoptosis of those PU.1 low-negative myeloma cell lines, U266 and KMS12PE, suggesting that down-regulation of PU.1 is necessary for myeloma cell growth. In addition, we reported that PU.1 is expressed in normal plasma cells and PU.1 is down-regulated in myeloma cells of some myeloma patients. Myeloma patients with low-to-negative PU.1 expression (lower 25th percentile of PU.1 expression level distribution among 30 patients we examined) may have poor prognosis compared to those with high PU.1 expression, although more patient samples have to be examined to define the significance of the relationship of PU.1 expression levels and prognosis. To elucidate the mechanisms of PU.1 induced cell growth arrest and apoptosis of myeloma cells, we next performed DNA microarray analysis to compare gene expression levels before and after PU.1 induction. We utilized Illumina Sentrix® Human-6 Expression BeadChip. Of 47296 genes, 479 genes were up-regulated (>2fold) and 1697 genes down-regulated (<0.5 fold) either day 1 or 3 after PU.1 induction in U266 cells. Among apoptosis related genes, TRAIL was highly up-regulated in both U266 and KMS12PE cell lines. Stably expressed siRNA for TRAIL partially inhibited apoptosis of U266 cells expressing PU.1, suggesting that TRAIL is related to PU.1 induced cell death of U266 cells. Among cell-cycle related genes, p21WAF1/CIP1 was found up-regulated in U266 cells, which was confirmed with protein levels. We are now examining the roles of the observed up-regulated genes in both U266 and KMS12PE myeloma cell lines.

Autocrine Regulation of Murine B Lymphocyte Growth by an IgM Antibody

Immunobiology ◽  
1992 ◽  
Vol 185 (2-4) ◽  
pp. 292-302 ◽  
Author(s):  
Ferenc Uher ◽  
Maria E. Alonso ◽  
Rudolf Mihalik ◽  
Éva Balogh ◽  
Janos Gergely
Keyword(s):  
B Lymphocyte ◽  
Igm Antibody ◽  
Autocrine Regulation ◽  
Lymphocyte Growth

Molecular control of B Lymphocyte growth and differentiation

Stem Cells ◽  
1994 ◽  
Vol 12 (3) ◽  
pp. 278-288 ◽  
Author(s):  
J. Banchereau ◽  
F. Brière ◽  
Y. J. Liu ◽  
F. Rousset
Keyword(s):  
B Lymphocyte ◽  
Molecular Control ◽  
Lymphocyte Growth

scholarly journals Down-regulation of BLIMP1α by the EBV oncogene, LMP-1, disrupts the plasma cell differentiation program and prevents viral replication in B cells: implications for the pathogenesis of EBV-associated B-cell lymphomas

Blood ◽  
2011 ◽  
Vol 117 (22) ◽  
pp. 5907-5917 ◽  
Author(s):  
Katerina Vrzalikova ◽  
Martina Vockerodt ◽  
Sarah Leonard ◽  
Andrew Bell ◽  
Wenbin Wei ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Virus Replication ◽  
Plasma Cell ◽  
Germinal Center ◽  
Lytic Cycle ◽  
Transformed Cells ◽  
Down Regulation ◽  
Plasma Cell Differentiation

AbstractAn important pathogenic event in Epstein-Barr virus (EBV)-associated lymphomas is the suppression of virus replication, which would otherwise lead to cell death. Because virus replication in B cells is intimately linked to their differentiation toward plasma cells, we asked whether the physiologic signals that drive normal B-cell differentiation are absent in EBV-transformed cells. We focused on BLIMP1α, a transcription factor that is required for plasma cell differentiation and that is inactivated in diffuse large B-cell lymphomas. We show that BLIMP1α expression is down-regulated after EBV infection of primary germinal center B cells and that the EBV oncogene, latent membrane protein-1 (LMP-1), is alone capable of inducing this down-regulation in these cells. Furthermore, the down-regulation of BLIMP1α by LMP-1 was accompanied by a partial disruption of the BLIMP1α transcriptional program, including the aberrant induction of MYC, the repression of which is required for terminal differentiation. Finally, we show that the ectopic expression of BLIMP1α in EBV-transformed cells can induce the viral lytic cycle. Our results suggest that LMP-1 expression in progenitor germinal center B cells could contribute to the pathogenesis of EBV-associated lymphomas by down-regulating BLIMP1α, in turn preventing plasma cell differentiation and induction of the viral lytic cycle.

scholarly journals Ligand-independent Signaling Functions for the B Lymphocyte Antigen Receptor and Their Role in Positive Selection during B Lymphopoiesis

2001 ◽  
Vol 194 (11) ◽  
pp. 1583-1596 ◽  
Author(s):  
Gregory Bannish ◽  
Ezequiel M. Fuentes-Pananá ◽  
John C. Cambier ◽  
Warren S. Pear ◽  
John G. Monroe
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Antigen Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Lymphopoiesis ◽  
Biologically Relevant ◽  
Developmental Progression

Signal transduction through the B cell antigen receptor (BCR) is determined by a balance of positive and negative regulators. This balance is shifted by aggregation that results from binding to extracellular ligand. Aggregation of the BCR is necessary for eliciting negative selection or activation by BCR-expressing B cells. However, ligand-independent signaling through intermediate and mature forms of the BCR has been postulated to regulate B cell development and peripheral homeostasis. To address the importance of ligand-independent BCR signaling functions and their regulation during B cell development, we have designed a model that allows us to isolate the basal signaling functions of immunoglobulin (Ig)α/Igβ-containing BCR complexes from those that are dependent upon ligand-mediated aggregation. In vivo, we find that basal signaling is sufficient to facilitate pro-B → pre-B cell transition and to generate immature/mature peripheral B cells. The ability to generate basal signals and to drive developmental progression were both dependent on plasma membrane association of Igα/Igβ complexes and intact immunoregulatory tyrosine activation motifs (ITAM), thereby establishing a correlation between these processes. We believe that these studies are the first to directly demonstrate biologically relevant basal signaling through the BCR where the ability to interact with both conventional as well as nonconventional extracellular ligands is eliminated.

Synergistic Cooperation Between T and B Lymphocytes from Old Mice in the Production of Auto-Anti-Idiotypic Antibody Regulation in Adult Irradiated Hosts

1982 ◽  
Vol 1 (1-2) ◽  
pp. 3-10 ◽  
Author(s):  
Myron R. Szewczuk
Keyword(s):  
B Cells ◽  
B Lymphocytes ◽  
B Lymphocyte ◽  
Intrinsic Property ◽  
Adoptive Cell Transfer ◽  
Cell Transfer ◽  
Lymphocyte Population ◽  
Thymus Cells ◽  
Old Mice ◽  
Idiotypic Antibody

ABSTRACTThe effect of age on the ability of B lymphocytes and thymus cells from donors of various ages to be capable of producing an anti-idiotype-blocked, hapten-augmentable PFC was studied by adoptive cell transfer techniques. Lethally irradiated mice were reconstituted with syngeneic B lymphocytes and thymus cells from donors of various ages. Recipients were immunized with trinitrophenylated bovine gamma globulin (TNP-BGG) one or seven days after cell transfer. Splenic IgG anti-TNP plaque-forming cell (PFC) responses were assayed in the absence and presence of hapten for anti-idiotype (Id)-blocked, hapten-augmentable PFC, 14 days after immunization. It was found that the B lymphocyte population from 2 month old donors together with thymus cells from donors of various ages (2 to 19 months) were incapable of reconstituting mice to produce anti-Id-blocked, hapten-augmentable PFC. Similar results were obtained when mice were reconstituted with thymus cells from 2-month-old donors together with B cells from donors of various ages (2 to 14 months). In contrast, mice reconstituted with B cells plus thymus cells from the same 8-month or older donors produced a significantly high percentage of anti-Id-block, hapten augmentable PFC. Mice reconstituted with B cells from 8 months or older donors plus thymus cells from donors of various ages (8 to 19) months also produced a significantly high percentage of hapten-augmentable PFC. Experiments with B cells and thymus cells from 2-or 8-month old donors parked in lethally irradiated 2-or 8-months old recipients for 7 days revealed that neither lymphocytes from old donors or old recipients were capable of inducing the appearance of anti-Id-blocked, hapten-augmentable PFC in the lymphocyte population from 2-month-old donors. Thus, the results of this study indicate syner-gistic co-operation between B lymphocytes and thymus cells from old donors for the production of auto-anti-idiotypic antibody regulation with age. This production of auto-anti-Id antibody with age seems not to be an induced maturation event but perhaps an intrinsic property unique to lymphocytes from old donors.

Characteristics of early murine B-lymphocyte precursors and their direct sensitivity to negative regulators

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2708-2715 ◽  
Author(s):  
Taku Kouro ◽  
Kay L. Medina ◽  
Kenji Oritani ◽  
Paul W. Kincade
Keyword(s):  
B Cells ◽  
Growth Factor ◽  
B Lymphocyte ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Transforming Growth Factor Β ◽  
Ki 67 ◽  
Differentiation Potential ◽  
Murine Bone Marrow ◽  
B Lineage

Abstract Recently, a collection of surface markers was exploited to isolate viable Lin− TdT+ cells from murine bone marrow. These early pro-B cells were enriched for B-lineage lymphocyte precursor activity measured by short-term culture and had little responsiveness to myeloid growth factors. Early precursors can be propagated with remarkably high cloning frequencies in stromal cell–free, serum-free cultures, permitting this analysis of direct regulatory factors. Expression of the interleukin-7 receptor (IL-7Rα) chain marks functional precursors and IL-7 is necessary for progression beyond the CD45RA+ CD19− stage. Efficient survival and differentiation were only observed when stem cell factor and Flt-3 ligand were also present. IL-7–responsive CD19+precursors are estrogen resistant. However, B-lineage differentiation was selectively abrogated when highly purified Lin− precursors were treated with hormone in the absence of stromal cells. In addition, early stages of B lymphopoiesis were arrested by limitin, a new interferon (IFN)–like cytokine as well as IFN-α, IFN-γ, or transforming growth factor β (TGF-β), but not by epidermal growth factor (EGF). Lin− TdT+early pro-B cells are shown here to be CD27+AA4.1+/−Ki-67+ Ly-6C−Ly-6A/Sca-1Lo/−Thy-1−CD43+CD4+/−CD16/32Lo/−CD44Hi and similar in some respects to the “common lymphoid progenitors” (CLP) identified by others. Although early pro-B cells have lost myeloid differentiation potential, transplantation experiments described here reveal that at least some can generate T lymphocytes. Of particular importance is the demonstration that a pivotal early stage of lymphopoiesis is directly sensitive to negative regulation by hormones and cytokines.

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