IgM-MM is predominantly a pre–germinal center disorder and has a distinct genomic and transcriptomic signature from WM

Blood ◽  
2021 ◽  
Vol 138 (20) ◽  
pp. 1980-1985
Author(s):  
Abdul Hamid Bazarbachi ◽  
Hervé Avet-Loiseau ◽  
Raphael Szalat ◽  
Anil Aktas Samur ◽  
Zachary Hunter ◽  
...  
Keyword(s):  
Germinal Center ◽  
Immunoglobulin M ◽  
Translocation Chromosome ◽  
Targeted Therapeutics ◽  
Class Switching ◽  
Key Characteristics ◽  
Bruton Tyrosine Kinase ◽  
Assessment And Treatment ◽  
Elevated Expression ◽  
Transcriptomic Signature

Abstract Immunoglobulin M (IgM) multiple myeloma (MM) is a rare disease subgroup. Its differentiation from other IgM-producing gammopathies such as Waldenström macroglobulinemia (WM) has not been well characterized but is essential for proper risk assessment and treatment. In this study, we investigated genomic and transcriptomic characteristics of IgM-MM samples using whole-genome and transcriptome sequencing to identify differentiating characteristics from non–IgM-MM and WM. Our results suggest that IgM-MM shares most of its defining structural variants and gene-expression profiling with MM, but has some key characteristics, including t(11;14) translocation, chromosome 6 and 13 deletion as well as distinct molecular and transcription-factor signatures. Furthermore, IgM-MM translocations were predominantly characterized by VHDHJH recombination-induced breakpoints, as opposed to the usual class-switching region breakpoints; coupled with its lack of class switching, these data favor a pre–germinal center origin. Finally, we found elevated expression of clinically relevant targets, including CD20 and Bruton tyrosine kinase, as well as high BCL2/BCL2L1 ratio in IgM-MM, providing potential for targeted therapeutics.

scholarly journals Germinal Center Initiation, Variable Gene Region Hypermutation, and Mutant B Cell Selection without Detectable Immune Complexes on Follicular Dendritic Cells

2000 ◽  
Vol 192 (7) ◽  
pp. 931-942 ◽  
Author(s):  
Lynn G. Hannum ◽  
Ann M. Haberman ◽  
Shannon M. Anderson ◽  
Mark J. Shlomchik
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
B Cell ◽  
Immune Complexes ◽  
Germinal Center ◽  
Serum Antibody ◽  
Cell Formation ◽  
Immunoglobulin M ◽  
Follicular Dendritic Cells ◽  
Follicular Dendritic

Serum antibody (Ab) can play several roles during B cell immune responses. Among these is to promote the deposition of immune complexes (ICs) on follicular dendritic cells (FDCs). ICs on FDCs are generally thought to be critical for normal germinal center (GC) formation and the development and selection of memory B cells. However, it has been very difficult to test these ideas. To determine directly whether FDC-bound complexes do indeed function in these roles, we have developed a transgenic (Tg) mouse in which all B lymphocytes produce only the membrane-bound form of immunoglobulin M. Immune Tg mice have 10,000-fold less specific Ab than wild-type mice and lack detectable ICs on FDCs. Nonetheless, primary immune responses and the GC reaction in these mice are robust, suggesting that ICs on FDCs do not play critical roles in immune response initiation and GC formation. Moreover, as indicated by the presence and pattern of somatic mutations, memory cell formation and selection appear normal in these IC-deficient GCs.

scholarly journals Modifications to a LATE MERISTEM IDENTITY1 gene are responsible for the major leaf shapes of Upland cotton (Gossypium hirsutum L.)

2016 ◽  
Vol 114 (1) ◽  
pp. E57-E66 ◽  
Author(s):  
Ryan J. Andres ◽  
Viktoriya Coneva ◽  
Margaret H. Frank ◽  
John R. Tuttle ◽  
Luis Fernando Samayoa ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Leaf Shape ◽  
Primary Source ◽  
Tetraploid Cotton ◽  
Virus Induced Gene Silencing ◽  
Unique Role ◽  
Leaf Formation ◽  
Elevated Expression ◽  
Transcriptomic Signature ◽  
Lobed Leaf

Leaf shape varies spectacularly among plants. Leaves are the primary source of photoassimilate in crop plants, and understanding the genetic basis of variation in leaf morphology is critical to improving agricultural productivity. Leaf shape played a unique role in cotton improvement, as breeders have selected for entire and lobed leaf morphs resulting from a single locus, okra (l-D1), which is responsible for the major leaf shapes in cotton. The l-D1 locus is not only of agricultural importance in cotton, but through pioneering chimeric and morphometric studies, it has contributed to fundamental knowledge about leaf development. Here we show that an HD-Zip transcription factor homologous to the LATE MERISTEM IDENTITY1 (LMI1) gene of Arabidopsis is the causal gene underlying the l-D1 locus. The classical okra leaf shape allele has a 133-bp tandem duplication in the promoter, correlated with elevated expression, whereas an 8-bp deletion in the third exon of the presumed wild-type normal allele causes a frame-shifted and truncated coding sequence. Our results indicate that subokra is the ancestral leaf shape of tetraploid cotton that gave rise to the okra allele and that normal is a derived mutant allele that came to predominate and define the leaf shape of cultivated cotton. Virus-induced gene silencing (VIGS) of the LMI1-like gene in an okra variety was sufficient to induce normal leaf formation. The developmental changes in leaves conferred by this gene are associated with a photosynthetic transcriptomic signature, substantiating its use by breeders to produce a superior cotton ideotype.

scholarly journals Intrinsic properties of germinal center-derived B cells promote their enhanced class switching to IgE

Allergy ◽  
2015 ◽  
Vol 70 (10) ◽  
pp. 1269-1277 ◽  
Author(s):  
F. Ramadani ◽  
N. Upton ◽  
P. Hobson ◽  
Y.-C. Chan ◽  
D. Mzinza ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Intrinsic Properties ◽  
Class Switching

scholarly journals Tolerance to Self Gangliosides Is the Major Factor Restricting the Antibody Response to Lipopolysaccharide Core Oligosaccharides in Campylobacter jejuni Strains Associated with Guillain-Barré Syndrome

2002 ◽  
Vol 70 (9) ◽  
pp. 5008-5018 ◽  
Author(s):  
Tyrone Bowes ◽  
Eric R. Wagner ◽  
Judith Boffey ◽  
Dawn Nicholl ◽  
Lynne Cochrane ◽  
...  
Keyword(s):  
T Cell ◽  
Campylobacter Jejuni ◽  
Knockout Mice ◽  
Cell Activation ◽  
Molecular Mimicry ◽  
Immunoglobulin M ◽  
Antibody Responses ◽  
Class Switching ◽  
Cd40 Ligation ◽  
Ganglioside Antibodies

ABSTRACT Guillain-Barré syndrome following Campylobacter jejuni infection is frequently associated with anti-ganglioside autoantibodies mediated by molecular mimicry with ganglioside-like oligosaccharides on bacterial lipopolysaccharide (LPS). The regulation of antibody responses to these T-cell-independent antigens is poorly understood, and only a minority of Campylobacter-infected individuals develop anti-ganglioside antibodies. This study investigates the response to gangliosides and LPS in strains of mice by using a range of immunization strategies. In normal mice following intraperitoneal immunization, antibody responses to gangliosides and LPS are low level but can be enhanced by the antigen format or coadministration of protein to recruit T-cell help. Class switching from the predominant immunoglobulin M (IgM) response to IgG3 occurs at low levels, suggesting B1-cell involvement. Systemic immunization results in poor responses. In GalNAc transferase knockout mice that lack all complex gangliosides and instead express high levels of GM3 and GD3, generation of anti-ganglioside antibodies upon immunization with either complex gangliosides or ganglioside-mimicking LPS is greatly enhanced and exhibits class switching to T-cell-dependent IgG isotypes and immunological memory, indicating that tolerance to self gangliosides is a major regulatory factor. Responses to GD3 are suppressed in knockout mice compared with wild-type mice, in which responses to GD3 are induced specifically by GD3 and as a result of polyclonal B-cell activation by LPS. The anti-ganglioside response generated in response to LPS is also dependent on the epitope density of the ganglioside mimicked and can be further manipulated by providing secondary signals via lipid A and CD40 ligation.

scholarly journals EBNA2 Interferes with the Germinal Center Phenotype by Downregulating BCL6 and TCL1 in Non-Hodgkin's Lymphoma Cells

2006 ◽  
Vol 81 (5) ◽  
pp. 2274-2282 ◽  
Author(s):  
Francesco Boccellato ◽  
Eleni Anastasiadou ◽  
Paola Rosato ◽  
Bettina Kempkes ◽  
Luigi Frati ◽  
...  
Keyword(s):  
Germinal Center ◽  
B Cell Lymphoma ◽  
Cell System ◽  
Negative Regulation ◽  
Immunoglobulin M ◽  
Transcriptional Level ◽  
Barr Virus ◽  
Hla Dr ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV)-negative diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma-derived cell lines infected in vitro with a recombinant EBV expressed type II/III latency. High expression of EBNA2 inversely correlated with expression of germinal center (GC)-associated genes, BCL6 and TCL1. The decreased expression of BCL6 appeared to be dose dependent, with almost complete abrogation in highly EBNA2-expressing clones. The role of EBNA2 in negative regulation of these genes was confirmed by transfection and in a hormone-inducible EBNA2 cell system. LMP1 transfection reduced expression of TCL1, but not of BCL6, in DLBCLs. The GC-associated gene repression was at the transcriptional level and CBF1 independent. A decrease in HLA-DR, surface immunoglobulin M, and class II transactivator expression and an increase in CCL3, a BCL6 repression target, was observed in EBNA2-expressing clones. Since BCL6 is indispensable for GC formation and somatic hypermutations (SHM), we suggest that the previously reported lack of SHM seen in EBNA2-expressing GC cells from infectious mononucleosis tonsils could be due to negative regulation of BCL6 by EBNA2. These findings suggest that EBNA2 interferes with the GC phenotype.

Long-Distance Tunneling Nanotubules Shuttle Viral Immunoglobulin Class Switch-Suppressing Factors from HIV-Infected Macrophages to B Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2278-2278
Author(s):  
Weifeng Xu ◽  
Paul A. Santini ◽  
Meimei Shan ◽  
Kang Chen ◽  
Susan C. Ball ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Fluorescent Protein ◽  
Small Gtpases ◽  
Immunoglobulin M ◽  
Switching Loss ◽  
Class Switching ◽  
Long Distance ◽  
Class Switch ◽  
Membrane Tethers

Abstract Class switching from immunoglobulin M (IgM) to IgG, IgA or IgE is central to immunity against viruses and requires activation of B cells by CD4+ T cells through CD40 ligand (CD40L). Human immunodeficiency virus (HIV) evades protective T cell-dependent IgG and IgA responses against viral proteins and vaccines through mechanisms that remain unknown. Recent findings from our lab suggested the involvement of negative factor (Nef), an HIV accessory protein that suppresses CD40 signaling in B cells. The present work addressed the mechanism by which Nef invades B cells. Fluorescence microscopy-based studies showed that accumulation of Nef in infected lymphoid follicles was associated with severe loss of activation-induced cytidine deaminase (AID), a Nef-targeted DNA-editing enzyme essential for class switching. Loss of follicular AID correlated with in vivo inactivation of CD40 signaling and formation of long-distance membrane tethers connecting Nef-positive B cells with HIV-infected macrophages. By combining confocal microscopy, videomicroscopy and electron microscopy with standard molecular biology techniques, we demonstrated that macrophages harboring HIV or expressing a chimeric Nef-green-fluorescent protein were capable of transferring Nef-containing cargos to B cells via long-distance, actin-propelled and energy-dependent membrane channels, including tunneling nanotubules. Transfer of Nef to B cells involved a clathrin-dependent pathway that required the guanine nucleotide exchange factor Vav as well as downstream Rho, Rac and Ccd42 small GTPases. This pathway led to Nef-mediated inhibition of CD40-induced AID expression and IgG and IgA class switching. In summary, our findings indicate that HIV evades T cell-dependent IgG and IgA responses by shuttling virus-encoded Ig class switch-suppressing factors from infected macrophages to non-infected B cells via long-range membrane tethers, including tunneling nanotubules.

scholarly journals B7-1 and B7-2 Have Overlapping, Critical Roles in Immunoglobulin Class Switching and Germinal Center Formation

Immunity ◽  
1997 ◽  
Vol 6 (3) ◽  
pp. 303-313 ◽  
Author(s):  
Frank Borriello ◽  
Michael P Sethna ◽  
Scott D Boyd ◽  
A.Nicola Schweitzer ◽  
Elizabeth A Tivol ◽  
...  
Keyword(s):  
Germinal Center ◽  
Class Switching ◽  
Immunoglobulin Class ◽  
Immunoglobulin Class Switching ◽  
Germinal Center Formation

scholarly journals Role of NF-κB in Cell Survival and Transcription of Latent Membrane Protein 1-Expressing or Epstein-Barr Virus Latency III-Infected Cells

2004 ◽  
Vol 78 (8) ◽  
pp. 4108-4119 ◽  
Author(s):  
Ellen D. Cahir-McFarland ◽  
Kara Carter ◽  
Andreas Rosenwald ◽  
Jena M. Giltnane ◽  
Sarah E. Henrickson ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Membrane Proteins ◽  
Germinal Center ◽  
Epstein Barr Virus ◽  
Immunoglobulin M ◽  
Barr Virus ◽  
Epstein Barr ◽  
Germinal Center B Cells

ABSTRACT Epstein-Barr virus (EBV) latency III infection converts B lymphocytes into lymphoblastoid cell lines (LCLs) by expressing EBV nuclear and membrane proteins, EBNAs, and latent membrane proteins (LMPs), which regulate transcription through Notch and tumor necrosis factor receptor pathways. The role of NF-κB in LMP1 and overall EBV latency III transcriptional effects was investigated by treating LCLs with BAY11-7082 (BAY11). BAY11 rapidly and irreversibly inhibited NF-κB, decreased mitochondrial membrane potential, induced apoptosis, and altered LCL gene expression. BAY11 effects were similar to those of an NF-κB inhibitor, ΔN-IκBα, in effecting decreased JNK1 expression and in microarray analyses. More than 80% of array elements that decreased with ΔN-IκBα expression decreased with BAY11 treatment. Newly identified NF-κB-induced, LMP1-induced, and EBV-induced genes included pleckstrin, Jun-B, c-FLIP, CIP4, and IκBε. Of 776 significantly changed array elements, 134 were fourfold upregulated in EBV latency III, and 74 were fourfold upregulated with LMP1 expression alone, whereas only 28 were more than fourfold downregulated by EBV latency III. EBV latency III-regulated gene products mediate cell migration (EBI2, CCR7, RGS1, RANTES, MIP1α, MIP1β, CXCR5, and RGS13), antigen presentation (major histocompatibility complex proteins and JAW1), mitogen-activated protein kinase pathway (DUSP5 and p62Dok), and interferon (IFN) signaling (IFN-γRα, IRF-4, and STAT1). Comparison of EBV latency III LCL gene expression to immunoglobulin M (IgM)-stimulated B cells, germinal-center B cells, and germinal-center-derived lymphomas clustered LCLs with IgM-stimulated B cells separately from germinal-center cells or germinal-center lymphoma cells. Expression of IRF-2, AIM1, ASK1, SNF2L2, and components of IFN signaling pathways further distinguished EBV latency III-infected B cells from IgM-stimulated or germinal-center B cells.

scholarly journals DNA rearrangement can account for in vitro switching to IgG1.

1993 ◽  
Vol 178 (4) ◽  
pp. 1381-1390 ◽  
Author(s):  
C C Chu ◽  
E E Max ◽  
W E Paul
Keyword(s):  
B Cells ◽  
B Lymphocytes ◽  
Cultured Cells ◽  
Surface Expression ◽  
Immunoglobulin M ◽  
Interleukin 4 ◽  
Class Switching ◽  
Dna Deletion ◽  
Alternative Processing

During immune responses, B lymphocytes may switch from the expression of immunoglobulin M (IgM) to the expression of another isotype (e.g., IgG, IgE, IgA). In stable hybridomas and myelomas expressing a "switched" (S) isotype, DNA deletions between S mu and a "downstream" S region (S region recombination) have been found. In primary B cells, studies of the molecular basis of switching have been limited by the ability to sensitively quantitate the amount of DNA deletion; such studies would be of interest because other nondeletional mechanisms (trans-splicing, alternative processing of a long transcript) have been proposed to account for isotype switching in certain circumstances. We have applied the digestion-circularization polymerase chain reaction (DC-PCR) technique to measure the amount of S region recombination that occurs in the course of class switching in primary B lymphocytes. Resting B cells were cultured in lipopolysaccharide (LPS) and interleukin 4 (IL-4) to stimulate switching to IgG1. These cells begin to express membrane IgG1 at day 2.5 of culture and reach maximum expression by day 4.5. DNA was prepared from cultured cells and analyzed for S mu-S gamma 1 rearrangement by DC-PCR. Chimeric switch regions, indicating S mu-S gamma 1 recombination, were detected in amounts that, in most cases, correlated with surface expression. Furthermore, when cells were sorted on the basis of surface IgG1 expression, a mean of at least one S mu-S gamma 1 rearrangement per cell was seen in five out of seven experiments. In general, the IgG1+ cells obtained at 4.5 and 5.5 d of culture had close to 2 S mu-S gamma 1 rearrangements per cell. In IgG1- cells, S mu-S gamma 1 rearrangements were detectable, but at frequencies substantially lower that in IgG1+ cells. Thus, these results indicate that DNA deletion accompanies class switching in normal B cells stimulated with LPS and IL-4.

An Overview on Targeting Legumain for Inhibiting Cancers.

2020 ◽  
Vol 26 ◽  
Author(s):  
Bandi Deepa Reddy ◽  
Narasimha M Beeraka ◽  
CH. M. Kumari Chitturi ◽  
SubbaRao V. Madhunapantula
Keyword(s):  
Tumor Cells ◽  
Cysteine Proteases ◽  
Targeted Therapeutics ◽  
Pharmacological Agents ◽  
Tumor Recognition ◽  
Elevated Expression ◽  
Proliferation In Vitro ◽  
Structure And Activity

: Legumain (LGMN; EC: 3.4.22.34), an asparaginyl endopeptidase (AEP) or asparaginyl carboxypeptidase (ACP), is a member of the C13 family of cysteine proteases. Elevated expression of LGMN is reported not only in the tumor cells of breast, prostate and liver but also in the macrophages of the tumor micro-environment. Hence, LGMN is considered as a key protein involved in the regulation of tumor angiogenesis, invasion and metastasis. Targeting LGMN using siRNA or pharmacological agents and peptides was reported to reduce cancer cells proliferation in vitro and shrink tumor size in vivo. Moreover, expression of LGMN is significantly lower in normal cells compared to tumor cells or tumor associated macrophages (TAMs), hence, legumain can be used as a marker for tumor recognition and targeting. Therefore, approaches inhibiting LGMN expression or activity are more viable, less toxic and help in developing the targeted therapeutics. However, to date, LGMN targeting strategies have not been well reported. In this review, an attempt was made to summarize articles pertaining to LGMN (a) structure and activity; (b) oncogenic nature; (c) pharmacological inhibitors; and (d) targeting approaches that inhibit tumor growth. Furthermore, a list of existing gaps in LGMN research is highlighted, which needs additional studies.

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