189 results match your criteria pre-bcr signaling

Dynamical modeling predicts an inflammation-inducible CXCR7+ B cell precursor with potential implications in lymphoid blockage pathologies.

PeerJ 2020 29;8:e9902. Epub 2020 Sep 29.

Centro de Investigación Biomédica de Oriente, Delegación Puebla, Instituto Mexicano del Seguro Social, Metepec, Puebla, Mexico.

Background: The blockage at the early B lymphoid cell development pathway within the bone marrow is tightly associated with hematopoietic and immune diseases, where the disruption of basal regulatory networks prevents the continuous replenishment of functional B cells. Dynamic computational models may be instrumental for the comprehensive understanding of mechanisms underlying complex differentiation processes and provide novel prediction/intervention platforms to reinvigorate the system.

Methods: By reconstructing a three-module regulatory network including genetic transcription, intracellular transduction, and microenvironment communication, we have investigated the early B lineage cell fate decisions in normal and pathological settings. Read More

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September 2020

EBF1 and Pax5 safeguard leukemic transformation by limiting IL-7 signaling, Myc expression, and folate metabolism.

Genes Dev 2020 Oct 1. Epub 2020 Oct 1.

Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.

and mutations are associated with the development of B progenitor acute lymphoblastic leukemia (B-ALL) in humans. To understand the molecular networks driving leukemia in the (dHet) mouse model for B-ALL, we interrogated the transcriptional profiles and chromatin status of leukemic cells, preleukemic dHet pro-B, and wild-type pro-B cells with the corresponding EBF1 and Pax5 cistromes. In dHet B-ALL cells, many EBF1 and Pax5 target genes encoding pre-BCR signaling components and transcription factors were down-regulated, whereas Myc and genes downstream from IL-7 signaling or associated with the folate pathway were up-regulated. Read More

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October 2020

-Glycan Branching Is Required for Development of Mature B Cells.

J Immunol 2020 08 26;205(3):630-636. Epub 2020 Jun 26.

Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697; and

Galectins have been implicated in inhibiting BCR signaling in mature B cells but promoting pre-BCR signaling during early development. Galectins bind to branched -glycans attached to cell surface glycoproteins to control the distribution, clustering, endocytosis, and signaling of surface glycoproteins. During T cell development, -glycan branching is required for positive selection of thymocytes, inhibiting both death by neglect and negative selection via enhanced surface retention of the CD4/CD8 coreceptors and limiting TCR clustering/signaling, respectively. Read More

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It Takes Three Receptors to Raise a B Cell.

Trends Immunol 2020 07 22;41(7):629-642. Epub 2020 May 22.

Section of Rheumatology, and Gwen Knapp Center for Lupus and Immunology Research, Department of Medicine, University of Chicago, IL 60637, USA. Electronic address:

As the unique source of diverse immunoglobulin repertoires, B lymphocytes are an indispensable part of humoral immunity. B cell progenitors progress through sequential and mutually exclusive states of proliferation and recombination, coordinated by cytokines and chemokines. Mutations affecting the crucial pre-B cell checkpoint result in immunodeficiency, autoimmunity, and leukemia. Read More

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Fc Receptor-Like 6 (FCRL6) Discloses Progenitor B Cell Heterogeneity That Correlates With Pre-BCR Dependent and Independent Pathways of Natural Antibody Selection.

Front Immunol 2020 14;11:82. Epub 2020 Feb 14.

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.

B-1a cells produce "natural" antibodies (Abs) to neutralize pathogens and clear neo self-antigens, but the fundamental selection mechanisms that shape their polyreactive repertoires are poorly understood. Here, we identified a B cell progenitor subset defined by Fc receptor-like 6 (FCRL6) expression, harboring innate-like defense, migration, and differentiation properties conducive for natural Ab generation. Compared to FCRL6 pro B cells, the repressed mitotic, DNA damage repair, and signaling activity of FCRL6 progenitors, yielded V repertoires with biased distal segment accessibility, constrained diversity, and hydrophobic and charged CDR-H3 sequences. Read More

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February 2021

Delineating Human B Cell Precursor Development With Genetically Identified PID Cases as a Model.

Front Immunol 2019 26;10:2680. Epub 2019 Nov 26.

Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.

B-cell precursors (BCP) arise from hematopoietic stem cells in bone marrow (BM). Identification and characterization of the different BCP subsets has contributed to the understanding of normal B-cell development. BCP first rearrange their immunoglobulin (Ig) heavy chain (IGH) genes to form the pre-B-cell receptor (pre-BCR) complex together with surrogate light chains. Read More

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November 2020

Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families.

J Clin Immunol 2020 01 6;40(1):96-104. Epub 2019 Nov 6.

Laboratory of Transmission, Control and Immunobiology of Infections, LR11IPT02 (LTCII), Institut Pasteur de Tunis, 13, place Pasteur, BP74, 1002, Tunis-Belvédère, Tunisia.

Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency characterized by absent peripheral B cells, severe hypogammaglobulinemia, and absent BTK gene mutations. In ARA, mutations occur in genes encoding the pre-B cell receptor (pre-BCR) or downstream signaling proteins. In this work, we used candidate gene and whole-exome sequencing to investigate the molecular basis of ARA in 6 patients from 4 consanguineous North-African families. Read More

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January 2020

CXCR4 signaling directs Igk recombination and the molecular mechanisms of late B lymphopoiesis.

Nat Immunol 2019 10 2;20(10):1393-1403. Epub 2019 Sep 2.

Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, IL, USA.

In B lymphopoiesis, activation of the pre-B cell antigen receptor (pre-BCR) is associated with both cell cycle exit and Igk recombination. Yet how the pre-BCR mediates these functions remains unclear. Here, we demonstrate that the pre-BCR initiates a feed-forward amplification loop mediated by the transcription factor interferon regulatory factor 4 and the chemokine receptor C-X-C motif chemokine receptor 4 (CXCR4). Read More

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October 2019

Crucial Role of Increased Arid3a at the Pre-B and Immature B Cell Stages for B1a Cell Generation.

Front Immunol 2019 15;10:457. Epub 2019 Mar 15.

Fox Chase Cancer Center, Philadelphia, PA, United States.

The Lin28bLet7 axis in fetal/neonatal development plays a role in promoting CD5 B1a cell generation as a B-1 B cell developmental outcome. Here we identify the Let7 target, Arid3a, as a crucial molecular effector of the B-1 cell developmental program. Arid3a expression is increased at pro-B cell stage and markedly increased at pre-B and immature B cell stages in the fetal/neonatal liver B-1 development relative to that in the Lin28bLet7 adult bone marrow (BM) B-2 cell development. Read More

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September 2020

The Role of the Pre-B Cell Receptor in B Cell Development, Repertoire Selection, and Tolerance.

Front Immunol 2018 15;9:2423. Epub 2018 Nov 15.

Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Around four decades ago, it had been observed that there were cell lines as well as cells in the fetal liver that expressed antibody μ heavy (μH) chains in the apparent absence of light chains. It was thus possible that these cells expressed another molecule(s), that assembled with μH chains. The ensuing studies led to the discovery of the pre-B cell receptor (pre-BCR), which is assembled from Ig μH and surrogate light (SL) chains, together with the signaling molecules Igα and β. Read More

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October 2019

CBP Modulates Sensitivity to Dasatinib in Pre-BCR Acute Lymphoblastic Leukemia.

Cancer Res 2018 11 27;78(22):6497-6508. Epub 2018 Sep 27.

Department of Pathology, Stanford University School of Medicine, Stanford, California.

Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR ALL. Read More

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November 2018

The endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice.

J Biol Chem 2018 08 15;293(33):12934-12944. Epub 2018 Jun 15.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611. Electronic address:

Humoral immunity involves multiple checkpoints that occur in B cell development, maturation, and activation. The pre-B-cell receptor (pre-BCR) is expressed following the productive recombination of the immunoglobulin heavy-chain gene, and sSignalsing through the pre-BCR are required for the differentiation of pre-B cells into immature B cells. However, the molecular mechanisms controlling the pre-BCR expression and signaling strength remain undefined. Read More

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c-Myb Coordinates Survival and the Expression of Genes That Are Critical for the Pre-BCR Checkpoint.

J Immunol 2018 05 13;200(10):3450-3463. Epub 2018 Apr 13.

Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908; and

The c-Myb transcription factor is required for adult hematopoiesis, yet little is known about c-Myb function during lineage-specific differentiation due to the embryonic lethality of -null mutations. We previously used tissue-specific inactivation of the murine locus to demonstrate that c-Myb is required for differentiation to the pro-B cell stage, survival during the pro-B cell stage, and the pro-B to pre-B cell transition during B lymphopoiesis. However, few downstream mediators of c-Myb-regulated function have been identified. Read More

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PI3K induces B-cell development and regulates B cell identity.

Sci Rep 2018 01 22;8(1):1327. Epub 2018 Jan 22.

Institute of Immunology, University Medical Center Ulm, 89081, Ulm, Germany.

Phosphoinositide-3 kinase (PI3K) signaling is important for the survival of numerous cell types and class IA of PI3K is specifically required for the development of B cells but not for T cell development. Here, we show that class IA PI3K-mediated signals induce the expression of the transcription factor Pax5, which plays a central role in B cell commitment and differentiation by activating the expression of central B cell-specific signaling proteins such as SLP-65 and CD19. Defective class IA PI3K function leads to reduction in Pax5 expression and prevents B cell development beyond the stage expressing the precursor B cell receptor (pre-BCR). Read More

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January 2018

MLL1 Promotes IL-7 Responsiveness and Survival during B Cell Differentiation.

J Immunol 2018 03 19;200(5):1682-1691. Epub 2018 Jan 19.

Hematology/Oncology/Bone Marrow Transplant Section, Department of Pediatrics, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045; and

B lymphocyte differentiation is an exquisitely regulated homeostatic process resulting in continuous production of appropriately selected B cells. Relatively small changes in gene expression can result in deregulation of this process, leading to acute lymphocytic leukemia (ALL), immune deficiency, or autoimmunity. Translocation of () often results in a pro-B cell ALL, but little is known about its role in normal B cell differentiation. Read More

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High STAP1 expression in DUX4-rearranged cases is not suitable as therapeutic target in pediatric B-cell precursor acute lymphoblastic leukemia.

Sci Rep 2018 01 12;8(1):693. Epub 2018 Jan 12.

Department of Pediatric Oncology/Hematology, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.

Approximately 25% of the pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases are genetically unclassified. More thorough elucidation of the pathobiology of these genetically unclassified ('B-other') cases may identify novel treatment options. We analyzed gene expression profiles of 572 pediatric BCP-ALL cases, representing all major ALL subtypes. Read More

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January 2018

Distorted antibody repertoire developed in the absence of pre-B cell receptor formation.

Biochem Biophys Res Commun 2018 01 27;495(1):1411-1417. Epub 2017 Nov 27.

Department of Immunology, National Institute of Infectious Diseases, Shinjuku, Tokyo 162-8640, Japan. Electronic address:

The pre-B cell receptor (pre-BCR), consisting of the μ heavy chain (μHC) and the surrogate light chain (SLC, Vpre-B and λ5), plays important roles during B cell development. The formation of the pre-BCR, which enables the nascent immunoglobulin HC to associate with the SLC, is considered a prerequisite for B cell development. However, a significant number of peripheral mature (leaky) B cells exist in SLC-deficient mice. Read More

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January 2018

Activation-induced cytidine deaminase prevents pro-B cell acute lymphoblastic leukemia by functioning as a negative regulator in Rag1 deficient pro-B cells.

Oncotarget 2017 Sep 7;8(44):75797-75807. Epub 2017 Sep 7.

Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Duesseldorf, Medical Faculty, Duesseldorf, Germany.

Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation and class switch recombination in mature B-cells, while AID was also shown to play a role in developing pre-BCR/BCR-positive B-cells of the bone marrow. To further elucidate a potential function of Aid in the bone marrow prior to V(D)J-recombination, we utilized an model which exerts a B-cell developmental arrest at the pro-B cell stage with low frequencies of pro-B cell acute lymphoblastic leukemia (pro-B ALL) development. Therefore, (AR) mice were crossed with Aid-deficient mice (ARA). Read More

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September 2017

The miR-15 family reinforces the transition from proliferation to differentiation in pre-B cells.

EMBO Rep 2017 09 13;18(9):1604-1617. Epub 2017 Jul 13.

Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria

Precursor B lymphocytes expand upon expression of a pre-B cell receptor (pre-BCR), but then transit into a resting state in which immunoglobulin light chain gene recombination is initiated. This bi-phasic sequence is orchestrated by the IL-7 receptor (IL-7R) and pre-BCR signaling, respectively, but little is known about microRNAs fine-tuning these events. Here, we show that pre-B cells lacking miR-15 family functions exhibit prolonged proliferation due to aberrant expression of the target genes cyclin E1 and D3. Read More

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September 2017

The transcription factor Gli3 promotes B cell development in fetal liver through repression of Shh.

J Exp Med 2017 Jul 22;214(7):2041-2058. Epub 2017 May 22.

Great Ormond Street Institute of Child Health, University College London, London, England, UK

Before birth, B cells develop in the fetal liver (FL). In this study, we show that Gli3 activity in the FL stroma is required for B cell development. In the Gli3-deficient FL, B cell development was reduced at multiple stages, whereas the Sonic hedgehog (Hh [Shh])-deficient FL showed increased B cell development, and Gli3 functioned to repress transcription. Read More

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Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival.

Nat Immunol 2017 06 3;18(6):694-704. Epub 2017 Apr 3.

Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.

The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCβ, NF-κB1 and IKAROS, to initiate B-ALL. Read More

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Ibrutinib inhibits pre-BCR B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK.

Blood 2017 03 28;129(9):1155-1165. Epub 2016 Dec 28.

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.

Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Read More

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Dynamic pre-BCR homodimers fine-tune autonomous survival signals in B cell precursor acute lymphoblastic leukemia.

Sci Signal 2016 11 29;9(456):ra116. Epub 2016 Nov 29.

Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.

The pre-B cell receptor (pre-BCR) is an immature form of the BCR critical for early B lymphocyte development. It is composed of the membrane-bound immunoglobulin (Ig) heavy chain, surrogate light chain components, and the signaling subunits Igα and Igβ. We developed monovalent quantum dot (QD)-labeled probes specific for Igβ to study the behavior of pre-BCRs engaged in autonomous, ligand-independent signaling in live B cells. Read More

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November 2016

Science Signaling Podcast for 29 November 2016: Pre-B cell receptor signaling in leukemia.

Sci Signal 2016 11 29;9(456):c23. Epub 2016 Nov 29.

Web Editor, Science Signaling, American Association for the Advancement of Science, 1200 New York Avenue, NW, Washington, DC 20005, USA.

This Podcast features an interview with Bridget Wilson, author of a Research Article that appears in the 29 November 2016 issue of Science Signaling, about pre-B cell receptor (pre-BCR) signaling in B cell precursor acute lymphoblastic leukemia (BCP-ALL). Signaling through the pre-BCR, an immature form of the BCR, promotes the survival of B cell progenitors and has been implicated in the pathology of BCP-ALL. Erasmus et al found that pre-BCRs formed transient homomeric complexes that correlated with pro-survival signaling. Read More

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November 2016

The Expression Pattern of the Pre-B Cell Receptor Components Correlates with Cellular Stage and Clinical Outcome in Acute Lymphoblastic Leukemia.

PLoS One 2016 9;11(9):e0162638. Epub 2016 Sep 9.

Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Precursor-B cell receptor (pre-BCR) signaling represents a crucial checkpoint at the pre-B cell stage. Aberrant pre-BCR signaling is considered as a key factor for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) development. BCP-ALL are believed to be arrested at the pre-BCR checkpoint independent of pre-BCR expression. Read More

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The Sel1L-Hrd1 Endoplasmic Reticulum-Associated Degradation Complex Manages a Key Checkpoint in B Cell Development.

Cell Rep 2016 09 25;16(10):2630-2640. Epub 2016 Aug 25.

Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Graduate Field of Immunology and Infectious Disease, Cornell University, Ithaca, NY 14853, USA. Electronic address:

Endoplasmic reticulum (ER)-associated degradation (ERAD) is a principal mechanism that targets ER-associated proteins for cytosolic proteasomal degradation. Here, our data demonstrate a critical role for the Sel1L-Hrd1 complex, the most conserved branch of ERAD, in early B cell development. Loss of Sel1L-Hrd1 ERAD in B cell precursors leads to a severe developmental block at the transition from large to small pre-B cells. Read More

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September 2016

Conditional Disruption of Raptor Reveals an Essential Role for mTORC1 in B Cell Development, Survival, and Metabolism.

J Immunol 2016 09 12;197(6):2250-60. Epub 2016 Aug 12.

Department of Comparative Medicine, University of Washington, Seattle, WA 98195; and

Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that coordinates nutrient and growth factor availability with cellular growth, division, and differentiation. Studies examining the roles of mTOR signaling in immune function revealed critical roles for mTOR in regulating T cell differentiation and function. However, few studies have investigated the roles of mTOR in early B cell development. Read More

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September 2016

PAX5 promotes pre-B cell proliferation by regulating the expression of pre-B cell receptor and its downstream signaling.

Mol Immunol 2016 05 24;73:1-9. Epub 2016 Mar 24.

College of Basic Medical Sciences, Dalian Medical University, 9-Western Section, Lvshun South Road, Dalian, Liaoning 116044, China. Electronic address:

PAX5 is indispensable for the commitment of early lymphoid progenitors to the B cell lineage as well as for the development of B cells. Although previous studies have indicated that the Pax5-conditional-knockout mouse exhibited dedifferentiation of mature B cell and the development of aggressive lymphomas, the changes of Pax5 gene expressions in pre-B cells have not been analyzed. To understand the functional importance of Pax5 gene in the proliferation and survival of pre-B cells, we established a Pax5-knockdown model using 70Z/3 pre-B cell line. Read More

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Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition.

Leukemia 2016 06 5;30(6):1246-54. Epub 2016 Feb 5.

Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Precursor-B-cell receptor (pre-BCR) signaling and spleen tyrosine kinase (SYK) recently were introduced as therapeutic targets for patients with B-cell acute lymphoblastic leukemia (B-ALL), but the importance of this pathway in B-ALL subsets and mechanism of downstream signaling have not fully been elucidated. Here, we provide new detailed insight into the mechanism of pre-BCR signaling in B-ALL. We compared the effects of pharmacological and genetic disruption of pre-BCR signaling in vitro and in mouse models for B-ALL, demonstrating exquisite dependency of pre-BCR(+) B-ALL, but not other B-ALL subsets, on this signaling pathway. Read More

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RAG-mediated DNA double-strand breaks activate a cell type-specific checkpoint to inhibit pre-B cell receptor signals.

J Exp Med 2016 Feb 1;213(2):209-23. Epub 2016 Feb 1.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

DNA double-strand breaks (DSBs) activate a canonical DNA damage response, including highly conserved cell cycle checkpoint pathways that prevent cells with DSBs from progressing through the cell cycle. In developing B cells, pre-B cell receptor (pre-BCR) signals initiate immunoglobulin light (Igl) chain gene assembly, leading to RAG-mediated DNA DSBs. The pre-BCR also promotes cell cycle entry, which could cause aberrant DSB repair and genome instability in pre-B cells. Read More

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February 2016