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Biological and clinical insight from analysis of the tumor B-cell 2 receptor structure and function in chronic lymphocytic Leukemia

Biological and clinical insight from analysis of the tumor B-cell 2 receptor structure and function in chronic lymphocytic Leukemia
Biological and clinical insight from analysis of the tumor B-cell 2 receptor structure and function in chronic lymphocytic Leukemia
The B-cell receptor (BCR) is essential to the behavior of the majority of normal and neoplastic mature B cells. The identification in 1999 of the two major CLL subsets expressing unmutated immunoglobulin (Ig) variable region genes (U-IGHV, U-CLL) of pre-germinal center origin and poor prognosis, and mutated IGHV (M-CLL) of post-germinal center origin and good prognosis, ignited intensive investigations on structure and function of the tumor BCR. These investigations have provided fundamental insight into CLL biology and eventually the mechanistic rationale for the development of successful therapies targeting BCR signaling. U-CLL and M-CLL are characterized by variable low surface IgM (sIgM) expression and signaling capacity. Variability of sIgM can in part be explained by chronic engagement with (auto)antigen at tissue sites. However, other environmental elements, genetic changes, and epigenetic signatures also contribute to the sIgM variability. The variable levels have consequences on the behavior of CLL, which is in a state of anergy with an indolent clinical course when sIgM expression is low, or pushed towards proliferation and a more aggressive clinical course when sIgM expression is high. Efficacy of therapies that target BTK may also be affected by the variable sIgM levels and signaling and, in part, explain the development of resistance.
B-cell receptor, BTK, Chronic lymphocytic leukemia, IGHV1-69, IGHV3-21, Ibrutinib, Immunogenetics, Surface IgM, Venetoclax
2072-6694
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Lanham, Stuart
28fdbbef-e3b6-4fdf-bd0f-4968eeb614d6
Chiodin, Giorgia
4b3e9525-b377-4d16-b69a-e05d2e7854fe
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Lanham, Stuart
28fdbbef-e3b6-4fdf-bd0f-4968eeb614d6
Chiodin, Giorgia
4b3e9525-b377-4d16-b69a-e05d2e7854fe

Forconi, Francesco, Lanham, Stuart and Chiodin, Giorgia (2022) Biological and clinical insight from analysis of the tumor B-cell 2 receptor structure and function in chronic lymphocytic Leukemia. Cancers, 28 (3), [663]. (doi:10.3390/cancers14030663).

Record type: Article

Abstract

The B-cell receptor (BCR) is essential to the behavior of the majority of normal and neoplastic mature B cells. The identification in 1999 of the two major CLL subsets expressing unmutated immunoglobulin (Ig) variable region genes (U-IGHV, U-CLL) of pre-germinal center origin and poor prognosis, and mutated IGHV (M-CLL) of post-germinal center origin and good prognosis, ignited intensive investigations on structure and function of the tumor BCR. These investigations have provided fundamental insight into CLL biology and eventually the mechanistic rationale for the development of successful therapies targeting BCR signaling. U-CLL and M-CLL are characterized by variable low surface IgM (sIgM) expression and signaling capacity. Variability of sIgM can in part be explained by chronic engagement with (auto)antigen at tissue sites. However, other environmental elements, genetic changes, and epigenetic signatures also contribute to the sIgM variability. The variable levels have consequences on the behavior of CLL, which is in a state of anergy with an indolent clinical course when sIgM expression is low, or pushed towards proliferation and a more aggressive clinical course when sIgM expression is high. Efficacy of therapies that target BTK may also be affected by the variable sIgM levels and signaling and, in part, explain the development of resistance.

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Accepted/In Press date: 20 January 2022
Published date: 28 January 2022
Additional Information: Funding Information: This work was funded by Blood Cancer UK (grant 18009), the Eyles Cancer Immunology Fellowship, Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/A18087, programme C2750/A23669, and BTERP project C36811/A29101). Acknowledgments: We are grateful to Freda Stevenson for her continued guidance and mentoring, Kathy Potter at the Faculty of Medicine Tissue Bank (Cancer Sciences Unit, University of Southampton) for the processing and storage of the primary CLL specimens, the entire CLL group at the University of Southampton for their regular scientific insight, and all the patients donating blood in support of our research. Funding Information: Funding: This work was funded by Blood Cancer UK (grant 18009), the Eyles Cancer Immunology Fellowship, Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/A18087, programme C2750/A23669, and BTERP project C36811/A29101). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2022 Elsevier B.V., All rights reserved.
Keywords: B-cell receptor, BTK, Chronic lymphocytic leukemia, IGHV1-69, IGHV3-21, Ibrutinib, Immunogenetics, Surface IgM, Venetoclax

Identifiers

Local EPrints ID: 455038
URI: http://eprints.soton.ac.uk/id/eprint/455038
ISSN: 2072-6694
PURE UUID: 5e5f6e05-734f-4217-950f-6683fb50365a
ORCID for Stuart Lanham: ORCID iD orcid.org/0000-0002-4516-264X

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Date deposited: 04 Mar 2022 17:39
Last modified: 28 Apr 2022 01:41

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Contributors

Author: Stuart Lanham ORCID iD
Author: Giorgia Chiodin

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