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Chronic lymphocytic leukemia

The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia

Leukemia volume 33, pages 287–298 (2019)Cite this article

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Abstract

B cell receptor (BCR) signaling is a central pathway promoting the survival and proliferation of normal and malignant B cells. Chronic lymphocytic leukemia (CLL) arises from mature B cells, expressing functional BCRs, mainly of immunoglobulin M (IgM) and IgD isotypes. Importantly, 30% of CLL patients express quasi-identical BCRs, the so-called “stereotyped” receptors, indicating the existence of common antigenic determinants, which may drive disease initiation and favor its progression. Although the antigenic specificity of IgM and IgD receptors is identical, there are distinct isotype-specific responses after IgM and IgD triggering. Here, we discuss the most important steps of normal B cell development, and highlight the importance of BCR signaling for CLL pathogenesis, with a focus on differences between IgM and IgD isotype signaling. We also highlight the main characteristics of CLL patient subsets, based on BCR stereotypy, and describe subset-specific BCR function and antigen-binding characteristics. Finally, we outline the key biologic and clinical responses to kinase inhibitor therapy, targeting the BCR-associated Bruton’s tyrosine kinase, phosphoinositide-3-kinase, and spleen tyrosine kinase in patients with CLL.

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Acknowledgements

The work was supported by a Leukemia and Lymphoma Society Scholar Award in Clinical Research (JAB), and by the CLL Global Research Foundation (CLLGRF). This research is also supported in part by the MD Anderson Cancer Center Support Grant CA016672, Associazione Italiana per la Ricerca sul Cancro AIRC Investigator grants #20246 (to PG), and Research Program AIRC 5 per mille #21198 (to PG), ERA-NET TRANSCAN-2 JTC 2014, GCH-CLL #143, MIUR-PRIN 2015ZMRFEA, Rome, Italy. EtH is a Special Fellow of the Leukemia and Lymphoma Society. MG is a recipient of Marie Sklodowska-Curie individual fellowship (grant agreement number 796491), funded by the European Union’s Horizon 2020 research and innovation programme.

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Author notes

  1. Elisa ten Hacken

    Present address: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA

  2. These authors contributed equally: Elisa ten Hacken, Maria Gounari.

Authors and Affiliations

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

    Elisa ten Hacken & Jan A. Burger

  2. Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece

    Maria Gounari

  3. Strategic Research Program on CLL, IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy

    Paolo Ghia

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  1. Elisa ten Hacken
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  4. Jan A. Burger
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Correspondence to Jan A. Burger.

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Conflict of interest

JAB received research funding from Pharmacyclics, Gilead, and Portola and is a consultant for Janssen. PG received honoraria from AbbVie, Acerta, Beigene, Gilead, Janssen and research grants from AbbVie, Janssen, Gilead, Novartis and Sunesis. The other authors declare that they have no conflict of interest.

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ten Hacken, E., Gounari, M., Ghia, P. et al. The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia. Leukemia 33, 287–298 (2019). https://doi.org/10.1038/s41375-018-0303-x

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  • DOI: https://doi.org/10.1038/s41375-018-0303-x

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