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B-cell receptor signaling in chronic lymphocytic leukemia.

B-cell receptor signaling in chronic lymphocytic leukemia.
B-cell receptor signaling in chronic lymphocytic leukemia.
The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies. Recombinatorial and mutational patterns in the clonal immunoglobulin (Ig) of chronic lymphocytic leukemia (CLL) have revealed 2 major IgMD-expressing subsets and an isotype-switched variant, each developing from distinct B-cell populations. Tracking of conserved stereotypic features of Ig variable regions characteristic of U-CLL indicate circulating naive B cells as the likely cells of origin. In CLL, engagement of the BCR by antigen occurs in vivo, leading to down-regulated expression and to an unanticipated modulation of glycosylation of surface IgM, visible in blood cells, especially in U-CLL. Modulated glycoforms of sIgM are signal competent and could bind to environmental lectins. U-CLL cases express more sIgM and have increased signal competence, linking differential signaling responses to clinical behavior. Mapping of BCR signaling pathways identifies targets for blockade, aimed to deprive CLL cells of survival and proliferative signals. New inhibitors of BCR signaling appear to have clinical activity. In this Perspective, we discuss the functional significance of the BCR in CLL, and we describe strategies to target BCR signaling as an emerging therapeutic approach.
0006-4971
4313-4320
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Krysov, Sergey
3a78eac1-af40-4b37-8576-3462947649be
Davies, Andrew J.
0fe6a40a-10d1-4ade-a7e6-d1dceb2470af
Steele, Andrew J
4349f6aa-2e3a-49a8-be73-7716056ae089
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Krysov, Sergey
3a78eac1-af40-4b37-8576-3462947649be
Davies, Andrew J.
0fe6a40a-10d1-4ade-a7e6-d1dceb2470af
Steele, Andrew J
4349f6aa-2e3a-49a8-be73-7716056ae089
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394

Stevenson, Freda K., Krysov, Sergey, Davies, Andrew J., Steele, Andrew J and Packham, Graham (2011) B-cell receptor signaling in chronic lymphocytic leukemia. Blood, 118 (16), 4313-4320. (doi:10.1182/blood-2011-06-338855). (PMID:21816833)

Record type: Article

Abstract

The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies. Recombinatorial and mutational patterns in the clonal immunoglobulin (Ig) of chronic lymphocytic leukemia (CLL) have revealed 2 major IgMD-expressing subsets and an isotype-switched variant, each developing from distinct B-cell populations. Tracking of conserved stereotypic features of Ig variable regions characteristic of U-CLL indicate circulating naive B cells as the likely cells of origin. In CLL, engagement of the BCR by antigen occurs in vivo, leading to down-regulated expression and to an unanticipated modulation of glycosylation of surface IgM, visible in blood cells, especially in U-CLL. Modulated glycoforms of sIgM are signal competent and could bind to environmental lectins. U-CLL cases express more sIgM and have increased signal competence, linking differential signaling responses to clinical behavior. Mapping of BCR signaling pathways identifies targets for blockade, aimed to deprive CLL cells of survival and proliferative signals. New inhibitors of BCR signaling appear to have clinical activity. In this Perspective, we discuss the functional significance of the BCR in CLL, and we describe strategies to target BCR signaling as an emerging therapeutic approach.

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Published date: 20 October 2011
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 337049
URI: http://eprints.soton.ac.uk/id/eprint/337049
ISSN: 0006-4971
PURE UUID: 5ce18d46-a1b9-4653-954d-fb4fb98af189
ORCID for Freda K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021
ORCID for Andrew J. Davies: ORCID iD orcid.org/0000-0002-7517-6938
ORCID for Andrew J Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 17 Apr 2012 09:33
Last modified: 15 Mar 2024 03:39

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Contributors

Author: Sergey Krysov
Author: Andrew J Steele ORCID iD
Author: Graham Packham ORCID iD

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