Precursor B Cell Receptor Signaling Activity Can Be Uncoupled from Surface Expression

Güloğlu, F. Betül; Roman, Christopher

doi:10.4049/jimmunol.176.11.6862

Cited by 15 publications

(10 citation statements)

References 68 publications

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“…Furthermore, studies using Ig heavy chains that are targeted to the endoplasmatic reticulum (ER) or the Golgi apparatus revealed that the signal initiation of the pre‐BCR may occur in parts from the trans‐Golgi network rather than the ER. This Golgi‐derived signal was sufficient to induce proliferation and upregulation of differentiation markers CD2 and CD22 and may explain the strong signaling effects of the pre‐BCR despite its low surface expression .…”

Section: Pre‐bcr Signaling and Function In Normal B‐cell Progenitorsmentioning

confidence: 99%

Mechanisms of pre‐B‐cell receptor checkpoint control and its oncogenic subversion in acute lymphoblastic leukemia

Buchner

Swaminathan

Chen

et al. 2014

Immunological Reviews

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Pre-B cells within the bone marrow represent the normal counterpart for most acute lymphoblastic leukemia (ALL). During normal early B-cell development, survival and proliferation signals are dominated by cytokines, particularly interleukin-7 (IL-7) for murine developing B cells. With expression of a functional pre-B-cell receptor (BCR), cytokine signaling is attenuated and the tonic/autonomous pre-BCR signaling pathway provides proliferation as well as differentiation signals. In this review, we first describe checkpoint mechanisms during normal B-cell development and then discuss how genetic lesions in these pathways function as oncogenic mimicries and allow transformed pre-B cells to bypass checkpoint control. We focus on cytokine receptor signaling that is mimicked by activating lesions in receptor subunits or downstream mediators as well as aberrant activation of non-B lymphoid cytokine receptors. Furthermore, we describe the molecular switch from cytokine receptor to pre-BCR signaling, how this pathway is of particular importance for certain ALL subtypes, and how pre-BCR signaling is engaged by genetic lesions, such as BCR-ABL1. We discuss the transcriptional control mechanisms downstream of both cytokine- and pre-BCR signaling and how normal checkpoint control mechanisms are circumvented in pre-B ALL. Finally, we highlight new therapeutic concepts for targeted inhibition of oncogenic cytokine or pre-BCR signaling pathways.

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Section: Pre‐bcr Signaling and Function In Normal B‐cell Progenitorsmentioning

confidence: 99%

Mechanisms of pre‐B‐cell receptor checkpoint control and its oncogenic subversion in acute lymphoblastic leukemia

Buchner

Swaminathan

Chen

et al. 2014

Immunological Reviews

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show abstract

“…In pre-B cells, the pre-B receptor acts from an intracellular location to generate most, if not all, signals that promote B cell differentiation (31). Similarly, intracellular IgM may be competent for signaling because the BCR assembles and associates with Ig␣ and Ig␤ in a post-endoplasmic reticulum (ER) compartment (32).…”

Section: Vh56r؉v 38c Receptors Are Enriched In Marginal Zone (Mz) B Cmentioning

confidence: 99%

Editing and escape from editing in anti-DNA B cells

Khan

Witsch

Goodman

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The time frame in which this mechanism operates is unknown, as is the compartment from which the signal is delivered. It is possible that the μ H chain‐mediated feedback signal that results in H chain allelic exclusion does not require surface expression, since μ H chains alone (in the absence of λ 5) can induce signalling, albeit at a low level, from the trans‐Golgi network [59]. Furthermore, it is possible that the signal for H chain allelic exclusion also induces cellular transition from the pre‐BI to the pre‐BII stage, since a functional H chain is sufficient for this process.…”

Section: Discussionmentioning

confidence: 99%

The pre‐B cell receptor checkpoint

et al. 2010

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a b s t r a c t B lymphocytes are essential antibody-producing cells of the immune system. During the development of progenitor B cells to mature B cells that express a membrane-bound antibody, the B cell receptor (BCR), the cells undergo selection at several checkpoints, which ensures that a diverse antibody repertoire is generated and that the BCRs recognise foreign-, but not self-, antigens. In this review, we consider the pre-BCR checkpoint. Mutations or alterations that affect this checkpoint underpin the development of pre-B cell leukemias, primary immunodeficiency, and possibly, systemic autoimmunity. Ó 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. The pre-B cell receptorFollowing the discovery of pre-B cells as precursors of B cells, the pre-B cell receptor (pre-BCR) was identified as a 'precursor' of the B cell receptor (BCR) [1][2][3]. The observation that the leukemic cells in most children with acute lymphoblastic leukemia were classified as pre-B cells [4], suggested the importance of this developmental stage. Whereas the BCR is assembled from the immunoglobulin (Ig) heavy (H) and light (L) chains, the pre-BCR is assembled from Ig H and surrogate L (SL) chains, the latter composed of the invariant k5 and VpreB polypeptides and having homology to bona fide Ig L chains [5][6][7][8]. Since the discovery of the pre-BCR, several groups have investigated the roles of the pre-BCR and SL chain [9]. It is clear that the pre-BCR is essential for B cells to develop normally, and that mutations or alterations affecting the pre-BCR underpins the development of cancer and immunodeficiency, and perhaps even autoimmunity [3,10,11]. Antibody diversityAntibodies are mediators of humoral immune responses, which participate in protection against pathogens. An antibody consists of an identical pair of H and L chains, each with a variable and a constant region, which are responsible for antigen recognition and effector functions, respectively (Fig. 1). Within the variable region, three hypervariable regions (known as 'complementarity determining regions'; CDR1-3) determine antigen recognition. This hypervariability is established at the DNA level through a somatic process termed V(D)J recombination, whereby variable (V), diversity (D), and joining (J) gene segments are recombined [12]. The mouse H chain locus, for instance, contains >100 functional V gene segments, >10 D segments, and four J gene segments [13]. Together with recombinations of the L chain loci, this diversity theoretically yields >10 12 different antibodies.The products of the lymphoid-specific recombination-activating genes (RAG1 and RAG2) are required for the recombination process [14,15]. These proteins bind the recombination signal sequences that flank each gene segment, and this is followed by a doublestrand break in the DNA, which is the initial event in the bringing together of the gene segments (Fig. 2).The diversity results from the V H gene segment itself (which encodes CDR1 and CDR2), the rec...

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Precursor B Cell Receptor Signaling Activity Can Be Uncoupled from Surface Expression

Cited by 15 publications

References 68 publications

Mechanisms of pre‐B‐cell receptor checkpoint control and its oncogenic subversion in acute lymphoblastic leukemia

Mechanisms of pre‐B‐cell receptor checkpoint control and its oncogenic subversion in acute lymphoblastic leukemia

Editing and escape from editing in anti-DNA B cells

The pre‐B cell receptor checkpoint

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