Binding of Free Immunoglobulin Light Chains to VpreB3 Inhibits Their Maturation and Secretion in Chicken B Cells

Rosnet, Olivier; Blanco-Betancourt, Carla; Grivel, Karine; Richter, Kirsten; Schiff, Claudine

doi:10.1074/jbc.m312169-a200

Cited by 32 publications

(30 citation statements)

References 50 publications

(42 reference statements)

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“…In this view, the assembly of a HC with the SLC replaces an older evolutionary state, when rearrangement of HC and LC genes still occurred simultaneously and before clonal expansion (57). In support of this idea, no orthologs for 5 and VpreB1/ VpreB2 genes were identified in chickens, in which HC and LC gene loci are simultaneously rearranged during early embryonic development (58,59). Chickens may not require SLC, since Ab diversity is generated predominantly by gene conversion in the bursa of Fabricius after the IgM-positive B lymphocyte population has been expanded (60).…”

Section: Discussionsupporting

confidence: 54%

A Unique Role for the λ5 Nonimmunoglobulin Tail in Early B Lymphocyte Development

Vettermann

Herrmann

Albert

et al. 2008

The Journal of Immunology

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Precursor BCR (pre-BCR) signaling governs proliferation and differentiation of pre-B cells during B lymphocyte development. However, it is controversial as to which parts of the pre-BCR, which is composed of Igμ H chain, surrogate L chain (SLC), and Igα-Igβ, are important for signal initiation. Here, we show in transgenic mice that the N-terminal non-Ig-like (unique) tail of the surrogate L chain component λ5 is critical for enhancing pre-BCR-induced proliferation signals. Pre-BCRs with a mutated λ5 unique tail are still transported to the cell surface, but they deliver only basal signals that trigger survival and differentiation of pre-B cells. Further, we demonstrate that the positively charged residues of the λ5 unique tail, which are required for pre-BCR self-oligomerization, can also mediate binding to stroma cell-associated self-Ags, such as heparan sulfate. These findings establish the λ5 unique tail as a pre-BCR-specific autoreactive signaling motif that could increase the size of the primary Ab repertoire by selectively expanding pre-B cells with functional Igμ H chains.

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Section: Discussionsupporting

confidence: 54%

A Unique Role for the λ5 Nonimmunoglobulin Tail in Early B Lymphocyte Development

Vettermann

Herrmann

Albert

et al. 2008

The Journal of Immunology

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“…Initial data indicated that VpreB3 is an important member of the pre-BCR complex in precursor B cells. 8,10 However, recent expression profiling studies detected VpreB3 transcripts in mature B cells and derived tumors. 6,19,20 In this study we show that VpreB3 is expressed by a subset of GCB as also demonstrated by its co-expression with germinal centerassociated molecules i.e.…”

Section: Discussionmentioning

confidence: 99%

“…4,8,9 It has been discussed whether VpreB3 has a role in the chaperoning and/or assembly of pre-BCR complexes prior to surface expression since VpreB3 has been detected in association with m heavy chain within the endoplasmic reticulum but not at the cell surface of pre-B-cell lines. 10 Nevertheless, the major biological functions of VpreB3 during B-cell development remain to be established, and whether VpreB3 protein is expressed or has biological roles beyond early B-cell development is unknown.…”

Section: Introductionmentioning

confidence: 99%

The pre-B-cell receptor associated protein VpreB3 is a useful diagnostic marker for identifying c-MYC translocated lymphomas

Rodig¹,

Kutok²,

Paterson³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. Background During B-cell development, precursor B cells transiently express the pre-B-cell receptor composed of m heavy chain complexed with VpreB and λ5 surrogate light chain polypeptides. Recent profiling studies unexpectedly revealed abundant transcripts of one member of the VpreB family, VpreB3, in a subset of mature B cells and Burkitt lymphoma. Design and Methods Here we used a novel antibody to investigate the normal expression pattern of VpreB3 protein in human hematopoietic and lymphoid tissues, and to determine whether VpreB3 could serve as a useful diagnostic biomarker for select B-cell lymphomas. Results We found that VpreB3 protein is normally expressed by precursor B cells in bone marrow and by a subset of normal germinal center B cells in secondary lymphoid organs. Among lymphoid malignancies, we found an association between VpreB3 expression and B-cell tumors with c-MYC abnormalities. VpreB3 was highly expressed in all cases of Burkitt lymphoma, whether of endemic or sporadic origin (44/44 cases, 100%), all cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (5/5 cases, 100%), and the majority of diffuse large B-cell lymphomas harboring a c-MYC translo-cation (15/18 cases, 83%). The expression of VpreB3 in diffuse large B-cell lymphomas without a c-MYC translocation was associated with c-MYC polysomy in 25/75 cases (33%) but only rarely observed in diffuse large B-cell lymphomas lacking a c-MYC abnormality (9/98 cases, 9%). Conclusions We conclude that for B-cell tumors with features suggesting a possible c-MYC translocation, such as intermediate to large cell size and high proliferation rate, the presence of VpreB3 should prompt subsequent confirmatory genetic testing, whereas the absence of VpreB3 is virtually always associated with wild-type c-MYC alleles. ABSTRACT 2056 haematologica | 2010; 95(12)

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“…VPS29 is part of the retromer complex responsible for the retrieval of mannose 6-phosphate receptors from the endosomal system to the Golgi (reviewed in Seaman, 2005). The chicken VpreB3 gene is thought to play a role in the maturation and secretion of IgL chain (Rosnet et al, 2004). Downstream of the C L exon we identified one predicted gene with similarity to carbonic anhydrase XV (CAXV, GenBank accession no.…”

Section: Identification Of Neighboring Genes In the Chicken Igl Locusmentioning

confidence: 99%

AID-mediated diversification within the IgL locus of chicken DT40 cells is restricted to the transcribed IgL gene

Gopal

Fugmann

2008

Molecular Immunology

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Somatic hypermutation (SHM) and gene conversion (GCV) are closely related processes that increase the diversity the primary immunoglobulin repertoire. In both processes the activationinduced cytidine deaminase (AID) converts cytosine residues to uracils within the DNA of the immunoglobulin (Ig) genes in a transcription-dependent manner, and subsequent error-prone repair processes lead to changes in the antigen recognition site of the encoded receptors. This activity is specifically recruited to the Ig loci by unknown mechanisms. Our analyses of the chicken B-cell line DT40, and derivatives thereof, now revealed that even the closest neighbors of the Ig light chain (IgL) gene are protected from AID activity, albeit being transcribed and thus acting as potential targets of AID. Our findings are in support of a model in which cis-acting DNA boundary elements restrict AID activity to the IgL locus and guard the genome in the vicinity of the IgL gene from deleterious mutations.

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Binding of Free Immunoglobulin Light Chains to VpreB3 Inhibits Their Maturation and Secretion in Chicken B Cells

Cited by 32 publications

References 50 publications

A Unique Role for the λ5 Nonimmunoglobulin Tail in Early B Lymphocyte Development

A Unique Role for the λ5 Nonimmunoglobulin Tail in Early B Lymphocyte Development

The pre-B-cell receptor associated protein VpreB3 is a useful diagnostic marker for identifying c-MYC translocated lymphomas

AID-mediated diversification within the IgL locus of chicken DT40 cells is restricted to the transcribed IgL gene

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