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

Sarah C. Pyfrom, Chaz C. Quinn, Hannah K. Dorando, Hong Luo and Jacqueline E. Payton
J Immunol June 22, 2020, ji2000088; DOI: https://doi.org/10.4049/jimmunol.2000088
Sarah C. Pyfrom
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
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Chaz C. Quinn
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
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Hannah K. Dorando
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
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Hong Luo
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
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Jacqueline E. Payton
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
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Key Points

  • lncRNA BCALM (AC099524.1) is B cell specific and highly expressed in human lymphomas.

  • BCALM is necessary for the interaction of signal transduction proteins PLD1 and AKAP9.

  • BCALM promotes negative feedback that downmodulates BCR-stimulated Ca+ signaling.

Abstract

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 γ 2 (PLCG2), a B cell–specific enzyme that stimulates intracellular Ca2+ signaling in response to BCR activation. AC099524.1 (B cell–associated 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 BCR-dependent cancers.

Footnotes

  • This work was supported by National Institutes of Health (NIH), National Cancer Institute (NCI) Grants CA156690 and CA188286, Washington University Institute of Clinical and Translational Sciences (ICTS) Grant UL1 TR000448 from the National Center for Advancing Translational Sciences (NCATS), and the Alvin J. Siteman Cancer Center (CA091842). Sequencing was provided by the Genome Technology Access Center, which is partially supported by NCI Cancer Center Support Grant P30 CA91842 to the Alvin J. Siteman Cancer Center and by ICTS/Clinical and Translational Science Award (CTSA) Grant UL1 TR000448 from the National Center for Research Resources (NCRR), a component of the NIH, and the NIH Roadmap for Medical Research. The ICTS is funded by the NIH NCATS CTSA program Grant UL1 TR002345.

  • This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. None of these sources had any role in data collection, analysis, interpretation, trial design, patient recruitment, writing the manuscript, the decision to submit the manuscript, or any other aspect pertinent to the study. None of the authors were paid to write the article by a company or any other agency. The corresponding author (J.E.P.) had full access to all of the data in the study and had final responsibility for the decision to submit for publication.

  • The sequences presented in this article have been submitted to the Gene Expression Omnibus under accession numbers GSE62246 and GSE132053.

  • The online version of this article contains supplemental material.

  • Received January 24, 2020.
  • Accepted May 27, 2020.
  • Copyright © 2020 by The American Association of Immunologists, Inc.

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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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BCALM (AC099524.1) Is a Human B Lymphocyte-Specific Long Noncoding RNA That Modulates B Cell Receptor–Mediated Calcium Signaling
Sarah C. Pyfrom, Chaz C. Quinn, Hannah K. Dorando, Hong Luo, Jacqueline E. Payton
The Journal of Immunology June 22, 2020, ji2000088; DOI: 10.4049/jimmunol.2000088

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BCALM (AC099524.1) Is a Human B Lymphocyte-Specific Long Noncoding RNA That Modulates B Cell Receptor–Mediated Calcium Signaling
Sarah C. Pyfrom, Chaz C. Quinn, Hannah K. Dorando, Hong Luo, Jacqueline E. Payton
The Journal of Immunology June 22, 2020, ji2000088; DOI: 10.4049/jimmunol.2000088
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Print ISSN 0022-1767        Online ISSN 1550-6606