scholarly journals B cells suppress medullary granulopoiesis by an extracellular glycosylation-dependent mechanism

2019 ◽  
Author(s):  
Eric E. Irons ◽  
Melissa M. Lee-Sundlov ◽  
Karin M. Hoffmeister ◽  
Joseph T.Y. Lau
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Elevated Blood ◽  
Hematopoietic Progenitors ◽  
Myeloma Cells ◽  
Human B Cells ◽  
Extrinsic Cues ◽  
Bone Marrow Niches ◽  
Dependent Mechanism ◽  
Dependent Interaction

AbstractThe immune response relies on the timely integration of cell-intrinsic processes with cell-extrinsic cues. During infection, B cells vacate the bone marrow for the emergency generation of granulocytes. However, it is unclear if cross-talk between B cells and neutrophils also encourages the return to homeostasis. Here, we report that B cells remodel glycans on hematopoietic progenitors to suppress granulopoiesis. Human B cells secrete active ST6Gal-1 sialyltransferase to modify the sialylation and Gr-1 expression of co-cultured hematopoietic progenitors. After adoptive transfer, total hematopoietic and B cells modified the sialylation of non-self cells and elevated blood ST6Gal-1. Mature IgD+ B cells co-localized with megakaryocytes to sialylated bone marrow niches, suggesting their role in medullary extrinsic sialylation. Finally, ST6Gal-1 expression in multiple myeloma cells negatively correlated with neutrophil abundance in human patients. Our results highlight the growing significance of extracellular glycoslytransferases as mediators of a novel glycan-dependent interaction between B cells and granulocytes.

scholarly journals B cells suppress medullary granulopoiesis by an extracellular glycosylation-dependent mechanism

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Eric E Irons ◽  
Melissa M Lee-Sundlov ◽  
Yuqi Zhu ◽  
Sriram Neelamegham ◽  
Karin M Hoffmeister ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
Progenitor Cell ◽  
Hematopoietic Progenitors ◽  
Myeloma Cells ◽  
Human B Cells ◽  
Extrinsic Cues ◽  
Bone Marrow Niches ◽  
Dependent Mechanism

The immune response relies on the integration of cell-intrinsic processes with cell-extrinsic cues. During infection, B cells vacate the marrow during emergency granulopoiesis but return upon restoration of homeostasis. Here we report a novel glycosylation-mediated crosstalk between marrow B cells and hematopoietic progenitors. Human B cells secrete active ST6GAL1 sialyltransferase that remodels progenitor cell surface glycans to suppress granulopoiesis. In mouse models, ST6GAL1 from B cells alters the sialylation profile of bone marrow populations, and mature IgD+ B cells were enriched in sialylated bone marrow niches. In clinical multiple myeloma, ST6GAL1 abundance in the multiple myeloma cells negatively correlated with neutrophil abundance. These observations highlight not only the ability of medullary B cells to influence blood cell production, but also the disruption to normal granulopoiesis by excessive ST6GAL1 in malignancy.

Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches

2008 ◽  
Vol 9 (4) ◽  
pp. 388-395 ◽  
Author(s):  
Anita Sapoznikov ◽  
Yael Pewzner-Jung ◽  
Vyacheslav Kalchenko ◽  
Rita Krauthgamer ◽  
Idit Shachar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
B Cells ◽  
Bone Marrow Niches ◽  
Critical Survival ◽  
Survival Signals

scholarly journals The Normal Counterpart of IgD Myeloma Cells in Germinal Center Displays Extensively Mutated IgVH Gene, Cμ–Cδ Switch, and λ Light Chain Expression

1998 ◽  
Vol 187 (8) ◽  
pp. 1169-1178 ◽  
Author(s):  
Christophe Arpin ◽  
Odette de Bouteiller ◽  
Diane Razanajaona ◽  
Isabelle Fugier-Vivier ◽  
Francine Brière ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Light Chain ◽  
Germinal Center ◽  
Plasma Cells ◽  
Precursor Cells ◽  
Memory B Cells ◽  
Hematopoietic Stem ◽  
Myeloma Cells ◽  
Λ Light Chain

Human myeloma are incurable hematologic cancers of immunoglobulin-secreting plasma cells in bone marrow. Although malignant plasma cells can be almost eradicated from the patient's bone marrow by chemotherapy, drug-resistant myeloma precursor cells persist in an apparently cryptic compartment. Controversy exists as to whether myeloma precursor cells are hematopoietic stem cells, pre–B cells, germinal center (GC) B cells, circulating memory cells, or plasma blasts. This situation reflects what has been a general problem in cancer research for years: how to compare a tumor with its normal counterpart. Although several studies have demonstrated somatically mutated immunoglobulin variable region genes in multiple myeloma, it is unclear if myeloma cells are derived from GCs or post-GC memory B cells. Immunoglobulin (Ig)D-secreting myeloma have two unique immunoglobulin features, including a biased λ light chain expression and a Cμ–Cδ isotype switch. Using surface markers, we have previously isolated a population of surface IgM−IgD+CD38+ GC B cells that carry the most impressive somatic mutation in their IgV genes. Here we show that this population of GC B cells displays the two molecular features of IgD-secreting myeloma cells: a biased λ light chain expression and a Cμ–Cδ isotype switch. The demonstration of these peculiar GC B cells to differentiate into IgD-secreting plasma cells but not memory B cells both in vivo and in vitro suggests that IgD-secreting plasma and myeloma cells are derived from GCs.

scholarly journals Heterogeneous expression of a novel MPC-1 antigen on myeloma cells: possible involvement of MPC-1 antigen in the adhesion of mature myeloma cells to bone marrow stromal cells

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3721-3729 ◽  
Author(s):  
N Huang ◽  
MM Kawano ◽  
H Harada ◽  
Y Harada ◽  
A Sakai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Cell Line ◽  
Bone Marrow Stromal Cells ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Myeloma Cell Line ◽  
Myeloma Cells ◽  
Human Myeloma Cell Line ◽  
Heterogeneous Expression

Abstract Recent immunophenotypic analysis has shown that the heterogeneous expression of the adhesion molecule VLA-5 classifies myeloma cells into VLA-5+ mature and VLA-5- immature subpopulations. To further clarify the two myeloma subpopulations, we generated a monoclonal antibody, MPC- 1, by immunizing mice with an adherent human myeloma cell line, KMS-5. The MPC-1 antibody recognized a 48-Kd surface antigen on KMS-5 but not on U-266, a nonadherent human myeloma cell line. Specificity characterization showed that MPC-1 antigen was expressed on mature myeloma cells, normal plasma cells, and mature B cells, whereas pre-B cells and germinal center B cells lacked its expression. Monocytes and a human bone marrow stromal cell line, KM102, also expressed this antigen. Two subclones of MPC-1+ VLA-5+ (KMS-5Ad) and MPC-1-VLA-5+ (KMS- 5NAd) were separated from the KMS-5 cell line. The KMS-5NAd adhered to KM102 more tightly than did the KMS-5NAd, and the U-266 (MPC-1-VLA-5-) displayed almost no adherence to the KM102. The adhesion of the KMS-5Ad was partially inhibited by the MPC-1 antibody. These results, taken together, suggest that the MPC-1 antigen serves as a differentiation marker for B-lineage cells, including plasma cells, and may function as an adhesion molecule involved in the interaction of mature myeloma cells with bone marrow stromal cells.

scholarly journals Plasma cells induce apoptosis of pre-B cells by interacting with bone marrow stromal cells

Blood ◽  
1996 ◽  
Vol 87 (8) ◽  
pp. 3375-3383 ◽  
Author(s):  
T Tsujimoto ◽  
IA Lisukov ◽  
N Huang ◽  
MS Mahmoud ◽  
MM Kawano
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Cell Lines ◽  
Stromal Cells ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
B Cell Survival

By using two-color phenotypic analysis with fluorescein isothiocyanate- anti-CD38 and phycoerythrin-anti-CD19 antibodies, we found that pre-B cells (CD38+CD19+) signifcantly decreased depending on the number of plasma cells (CD38++CD19+) in the bone marrow (BM) in the cases with BM plasmacytosis, such as myelomas and even polyclonal gammopathy. To clarify how plasma cells suppress survival of pre-B cells, we examined the effect of plasma cells on the survival of pre-B cells with or without BM-derived stromal cells in vitro. Pre-B cells alone rapidly entered apoptosis, but interleukin-7 (IL-7), a BM stromal cell line (KM- 102), or culture supernatants of KM-102 cells could support pre-B cell survival. On the other hand, inhibitory factors such as transforming growth factor-beta1 (TGF-beta1) and macrophage inflammatory protein- 1beta (MIP-1beta) could suppress survival of pre-B cells even in the presence of IL-7. Plasma cells alone could not suppress survival of pre- B cells in the presence of IL-7, but coculture of plasma cells with KM- 102 cells or primary BM stromal cells induced apoptosis of pre-B cells. Supernatants of coculture with KM-102 and myeloma cell lines (KMS-5) also could suppress survival of pre-B cells. Furthermore, we examined the expression of IL-7, TGF-beta1, and MIP-1beta mRNA in KM-102 cells and primary stromal cells cocultured with myeloma cell lines (KMS-5). In these cells, IL-7 mRNA was downregulated, but the expression of TGF- beta1 and MIP-1beta mRNA was augmented. Therefore, these results suggest that BM-derived stromal cells attached to plasma (myeloma) cells were modulated to secrete lesser levels of supporting factor (IL- 7) and higher levels of inhibitory factors (TGF-beta1 and MIP-1beta) for pre-B cell survival, which could explain why the increased number of plasma (myeloma) cells induced suppression of pre-B cells in the BM. This phenomenon may represent a feedback loop between pre-B cells and plasma cells via BM stromal cells in the BM.

scholarly journals Eosinophils and Megakaryocytes Support the Early Growth of Murine MOPC315 Myeloma Cells in Their Bone Marrow Niches

PLoS ONE ◽  
2014 ◽  
Vol 9 (10) ◽  
pp. e109018 ◽  
Author(s):  
David Wong ◽  
Oliver Winter ◽  
Christina Hartig ◽  
Svenja Siebels ◽  
Martin Szyska ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Early Growth ◽  
Myeloma Cells ◽  
Bone Marrow Niches

A Novel Role For Histone Deacetylase 11 (HDAC11) In Plasma Cell Differentation and Survival

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1907-1907
Author(s):  
Eva Sahakian ◽  
Jason B. Brayer ◽  
John Powers ◽  
Mark Meads ◽  
Allison Distler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Myeloma Cells ◽  
Peripheral Blood Plasma

Abstract The role of HDACs in cellular biology, initially limited to their effects upon histones, is now appreciated to encompass more complex regulatory functions that are dependent on their tissue expression, cellular compartment distribution, and the stage of cellular differentiation. Recently, our group has demonstrated that the newest member of the HDAC family of enzymes, HDAC11, is an important regulator of IL-10 gene expression in myeloid cells (Villagra A Nat Immunol. 2009). The role of this specific HDAC in B-cell development and differentiation is however unknown. To answer this question, we have utilized a HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allows the monitoring of the dynamic changes in HDAC11 gene expression/promoter activity in B-cells at different maturation stages (Heinz, N Nat. Rev. Neuroscience 2001). First, common lymphoid progenitors are devoid of HDAC11 transcriptional activation as indicated by eGFP expression. In the bone marrow, expression of eGFP moderately increases in Pro-B-cells and transitions to the Pre- and Immature B-cells respectively. Expression of eGFP doubles in the B-1 stage of differentiation in the periphery. Of note, examination of both the bone marrow and peripheral blood plasma cell compartment demonstrated increased expression of eGFP/HDAC11 mRNA at the steady-state. These results were confirmed in plasma cells isolated from normal human subjects in which HDAC11 mRNA expression was demonstrated. Strikingly, analysis of primary human multiple myeloma cells demonstrated a significantly higher HDAC11 mRNA expression in malignant cells as compared to normal plasma cells. Similar results were observed in 4/5 myeloma cell lines suggesting that perhaps HDAC11 expression might provide survival advantage to malignant plasma cells. Support to this hypothesis was further provided by studies in HDAC11KO mice in which we observed a 50% decrease in plasma cells in both the bone marrow and peripheral blood plasma cell compartments relative to wild-type mice. Taken together, we have unveiled a previously unknown role for HDAC11 in plasma cell differentiation and survival. The additional demonstration that HDAC11 is overexpressed in primary human myeloma cells provide the framework for specifically targeting this HDAC in multiple myeloma. Disclosures: Alsina: Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Baz:Celgene Corporation: Research Funding; Millenium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding.

scholarly journals Hematopoietic supportive functions of mouse bone marrow and fetal liver microenvironment: dissection of granulocyte, B-lymphocyte, and hematopoietic progenitor support at the stroma cell clone level

Blood ◽  
1996 ◽  
Vol 87 (11) ◽  
pp. 4596-4606 ◽  
Author(s):  
C Friedrich ◽  
E Zausch ◽  
SP Sugrue ◽  
JC Gutierrez-Ramos
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Adhesion Molecule ◽  
Stromal Cell ◽  
Cell Clone ◽  
Fetal Liver ◽  
Hematopoietic Progenitors ◽  
Cell Clones ◽  
Stimulating Factor

We dissected the functions of the microenvironment of bone marrow (BM) and fetal liver (FL) at the cellular level by cloning individual stromal calls and characterizing their phenotypical and functional features. Stromal cell clones derived from FL are large in size (mean forward light scatter intensity [mFSC] of 450), express the surface antigen Thy-1 but not Sca-1 and 6 out of 6 are able to differentiate into fat accumulating adipocytes. BM derived stromal cell clones are either small (mFSC of 250) or large (mFSC of 450), express Sca-1 but not Thy-1 and only 2 out of 7 differentiate towards adipocytes. Heterogeneity in terms of vascular adhesion molecule-1, intracellular adhesion molecule-1 and heat stable antigen expression was found among the different cell clones. Functional assays using long- and short-term cocultures of stromal and hematopoietic calls revealed: (1) the capacity of 8 out of 12 stromal cell clones to support the expansion of primitive hematopoietic progenitors (colony forming unit spleen day 12) more than 10 weeks. Fat accumulation but not expression of stem cell factor by stromal cells did correlate with this supportive function. (2) Better support of granulocyte maturation and proliferation by BM- compared to FL-derived stromal cell clones. However, stromal cell clones from both organs expressed macrophage-colony stimulating factor. (3) The ability of 4 out of 12 stromal cell clones (derived from both, FL and BM) to support the expansion of Interleukin-7 dependent pre-B cells from the BM. Pre-B cell growth stimulating factor was not restricted to supporters. (4) Mutual exclusiveness of myeloid and lymphoid support in that a given stromal cell clone supported either pre B-cell or granulocyte expansion. Experiments comparing the support of BM- and FL-derived hematopoietic progenitors showed identical responses of late (B220+/c-kit-) but strikingly different responses of early (B220+/c-kit+) pre-B cells, revealing different proliferation requirements for FL- versus BM- derived early pre-B cells in vitro.

Abstract P191: The Origin and Fate of Renin Progenitors During Hematopoiesis

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Brian C Belyea ◽  
Fang Xu ◽  
Maria Luisa S Sequeira-Lopez ◽  
R. Ariel Gomez
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
B Cells ◽  
B Lymphocytes ◽  
Fetal Liver ◽  
Adult Life ◽  
Yolk Sac ◽  
Surface Markers ◽  
Cell Surface Markers ◽  
Hematopoietic Progenitors

Our lab previously discovered the presence of novel renin-expressing progenitors within the hematopoietic system. These progenitors have cell surface markers, gene expression, and growth characteristics of B lymphocytes. Further, these cells represent a subset of total B lymphocytes, are numerous at birth, and diminish with age, suggesting renin expression may be prominent during embryonic hematopoiesis. However, it is unknown when renin progenitors first appear and what function they serve during hematopoietic development. In this study, we sought to further define the temporal appearance, identity, and evolution of renin progenitors throughout hematopoietic ontogeny. We used in vivo lineage-tracing techniques, flow cytometry, immunofluorescence, and polymerase chain reaction (PCR) analysis to investigate the origin and fate of renin hematopoietic progenitors. We found that renin expressing hematopoietic progenitors first appear within the yolk sac during mid gestation (E11.5 by PCR and E12.5 by flow cytometry) and peak in number at E13.5 (14.9 ± 4.8% of nucleated single cells by flow cytometry). Subsequently, renin lineage cells leave the yolk sac and colonize the fetal liver and spleen at E15.5. In the fetal liver and fetal spleen, renin lineage cells express B cell surface markers including CD19 and CD43, however they have dim B220 expression, consistent with a B-1 progenitor immunophenotype. Renin lineage cells within the bone marrow, spleen, and peripheral blood peak in number shortly after birth and then decrease with post-natal age and have a phenotype consistent with B-2 B lymphocytes (B220 + CD19 + CD23 + CD11b - ). Conversely, renin progenitors in the peritoneal cavity persist throughout adult life as B-1 B cells (B220 dim CD19 + CD23 - CD11b + ). These studies suggest that renin progenitors originate within the yolk sac during the initial wave of primitive B lymphopoiesis and then expand to the fetal liver and spleen prior to the development of definitive hematopoiesis. Renin-lineage cells persist during adult life as B-1 B cells in the peritoneal cavity and, to a lesser extent, as B-2 B cells in the bone marrow, spleen, and peripheral blood. The function of these renin progenitors is currently being investigated.

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