The regulators of BCR signaling during B cell activation

Wen, Yue; Jing, Yukai; Lü, Yang; Kang, Danqing; Jiang, Panpan; Li, Na; Cheng, Jiali; Li, Jingwen; Li, Xingbo; Peng, Zican; Sun, Xizi; Miller, Heather; Sui, Zhiwei; Gong, Quan; Ren, Boxu; Yin, Wei; Liu, Chaohong

doi:10.1097/bs9.0000000000000026

Cited by 31 publications

(24 citation statements)

References 174 publications

(176 reference statements)

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“…Acalabrutinib is well-tolerated and associated with low rates of treatment discontinuation due to AEs [8,9,18], which may provide some advantages in routine practice. However, patients taking proton-pump inhibitors might have impaired absorption of acalabrutinib (7).…”

Section: Discussionmentioning

confidence: 99%

“…In normal B cells, BCR ligation first induces activation, proliferation, and expansion. Certain B cells generate plasma cells, while others become anergic or undergo apoptosis ( 17 , 18 ). Following antigen stimulation and activation, certain B cells become memory B cells, and stop proliferation and differentiation ( 18 ).…”

Section: Molecular Mechanisms Of Btk Inhibition For the Treatment Of Cll/sllmentioning

confidence: 99%

“…Certain B cells generate plasma cells, while others become anergic or undergo apoptosis ( 17 , 18 ). Following antigen stimulation and activation, certain B cells become memory B cells, and stop proliferation and differentiation ( 18 ). When these memory B cells subsequently re-encounter the same antigen, they are activated and proliferate and differentiate into plasma cells ( 18 ).…”

Section: Molecular Mechanisms Of Btk Inhibition For the Treatment Of Cll/sllmentioning

confidence: 99%

“…Following antigen stimulation and activation, certain B cells become memory B cells, and stop proliferation and differentiation ( 18 ). When these memory B cells subsequently re-encounter the same antigen, they are activated and proliferate and differentiate into plasma cells ( 18 ). In CLL, there is chronic stimulation through the BCR-signaling pathway leading to proliferation, propagation, and increased prosurvival signals, contributing to expansion and prolonged survival of clonal B cells ( 19 ).…”

Section: Molecular Mechanisms Of Btk Inhibition For the Treatment Of Cll/sllmentioning

confidence: 99%

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Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice

O’Brien¹,

Brown

Byrd

et al. 2021

Front. Oncol.

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Bruton tyrosine kinase (BTK) inhibitors represent an important therapeutic advancement for B cell malignancies. Ibrutinib, the first-in-class BTK inhibitor, is approved by the US FDA to treat patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL; after ≥1 prior therapy); and by the European Medicines Agency (EMA) for adult patients with relapsed/refractory (R/R) MCL and patients with CLL. Ibrutinib treatment can be limited by adverse events (AEs) including atrial fibrillation, arthralgias, rash, diarrhea, and bleeding events, leading to drug discontinuation in 4%–26% of patients. Acalabrutinib, a second-generation BTK inhibitor, is approved by the FDA to treat adult patients with CLL/SLL or MCL (relapsed after 1 prior therapy); and by the EMA to treat adult patients with CLL or R/R MCL. The most common AE associated with acalabrutinib is headache of limited duration, which occurs in 22%–51% of patients, and is mainly grade 1–2 in severity, with only 1% of patients experiencing grade ≥3 headache. Furthermore, acalabrutinib is associated with a low incidence of atrial fibrillation. Zanubrutinib, a selective next-generation covalent BTK inhibitor, is approved by the FDA to treat adult patients with MCL who have received ≥1 prior therapy, and is under investigation for the treatment of patients with CLL. In the phase 3 SEQUOIA trial in patients with CLL, the most common grade ≥3 AEs were neutropenia/neutrophil count decreased and infections. This review provides an overview of BTK inhibitor-related AEs in patients with CLL, and strategies for their management.

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Section: Discussionmentioning

confidence: 99%

Section: Molecular Mechanisms Of Btk Inhibition For the Treatment Of Cll/sllmentioning

confidence: 99%

Section: Molecular Mechanisms Of Btk Inhibition For the Treatment Of Cll/sllmentioning

confidence: 99%

Section: Molecular Mechanisms Of Btk Inhibition For the Treatment Of Cll/sllmentioning

confidence: 99%

See 2 more Smart Citations

Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice

O’Brien¹,

Brown

Byrd

et al. 2021

Front. Oncol.

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“…In mature B lymphocytes, binding of Ag to the BCR activates signaling pathways and transcription factors that change gene expression, driving differentiation, survival, and proliferation (69,70). Perturbation of these pathways is the hallmark of B cell cancers, but the underlying mechanisms remain incompletely defined (71)(72)(73)(74)(75).…”

Section: Discussionmentioning

confidence: 99%

BCALM (AC099524.1) Is a Human B Lymphocyte–Specific Long Noncoding RNA That Modulates B Cell Receptor–Mediated Calcium Signaling

Pyfrom

Quinn

Dorando

et al. 2020

The Journal of Immunology

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Of the thousands of long noncoding RNAs (lncRNA) identified in lymphocytes, very few have defined functions. In this study, we report the discovery and functional elucidation of a human B cell-specific lncRNA with high levels of expression in three types of B cell cancer and normal B cells. The AC099524.1 gene is upstream of the gene encoding the B cell-specific phospholipase C g 2 (PLCG2), a B cell-specific enzyme that stimulates intracellular Ca 2+ signaling in response to BCR activation. AC099524.1 (B cellassociated lncRNA modulator of BCR-mediated Ca + signaling [BCALM]) transcripts are localized in the cytoplasm and, as expected, CRISPR/Cas9 knockout of AC099524.1 did not affect PLCG2 mRNA or protein expression. lncRNA interactome, RNA immunoprecipitation, and coimmunoprecipitation studies identified BCALM-interacting proteins in B cells, including phospholipase D 1 (PLD1), and kinase adaptor proteins AKAP9 (AKAP450) and AKAP13 (AKAP-Lbc). These two AKAP proteins form signaling complexes containing protein kinases A and C, which phosphorylate and activate PLD1 to produce phosphatidic acid (PA). BCR stimulation of BCALM-deficient B cells resulted in decreased PLD1 phosphorylation and increased intracellular Ca + flux relative to wild-type cells. These results suggest that BCALM promotes negative feedback that downmodulates BCR-mediated Ca + signaling by promoting phosphorylation of PLD1 by AKAP-associated kinases, enhancing production of PA. PA activates SHP-1, which negatively regulates BCR signaling. We propose the name BCALM for B-Cell Associated LncRNA Modulator of BCR-mediated Ca + signaling. Our findings suggest a new, to our knowledge, paradigm for lncRNA-mediated modulation of lymphocyte activation and signaling, with implications for B cell immune response and BCRdependent cancers.

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Dysregulated plasma autoantibodies are associated with B cell dysfunction in young Arab children with autism spectrum disorder in Qatar

Ltaief,

Nour‐Eldine,

Manaph

et al. 2024

Autism Research

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and communication, as well as the occurrence of stereotyped and repetitive behaviors. Previous studies have provided solid evidence of dysregulated immune system in ASD; however, limited studies have investigated autoantibody profiles in individuals with ASD. This study aims to screen plasma autoantibodies in a well‐defined cohort of young children with ASD (n = 100) and their matched controls (n = 60) utilizing a high‐throughput KoRectly Expressed (KREX) i‐Ome protein‐array technology. We identified differential protein expression of 16 autoantibodies in ASD, which were correlated with differential gene expression of these markers in independent ASD cohorts. Meanwhile, we identified a distinct list of 33 autoantibodies associated with ASD severity; several of which were correlated with maternal age and birth weight in ASD. In addition, we found dysregulated numbers of circulating B cells and activated HLADR+ B cells in ASD, which were correlated with altered levels of several autoantibodies. Further in‐depth analysis of B cell subpopulations revealed an increased frequency of activated naïve B cells in ASD, as well as an association of resting naïve B cells and transitional B cells with ASD severity. Pathway enrichment analysis revealed disrupted MAPK signaling in ASD, suggesting a potential relevance of this pathway to altered autoantibodies and B cell dysfunction in ASD. Finally, we found that a combination of eight autoantibodies associated with ASD severity showed an area under the curve (ROC‐AUC) of 0.937 (95% CI = 0.890, 0.983; p < 0.001), which demonstrated the diagnostic accuracy of the eight‐marker signature in the severity classification of ASD cases. Overall, this study determined dysregulated autoantibody profiles and B cell dysfunction in children with ASD and identified an eight‐autoantibody panel for ASD severity classification.

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The regulators of BCR signaling during B cell activation

Cited by 31 publications

References 174 publications

Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice

Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice

BCALM (AC099524.1) Is a Human B Lymphocyte–Specific Long Noncoding RNA That Modulates B Cell Receptor–Mediated Calcium Signaling

Dysregulated plasma autoantibodies are associated with B cell dysfunction in young Arab children with autism spectrum disorder in Qatar

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