The meaning and relevance of B-cell receptor structure and function in chronic lymphocytic leukemia
The meaning and relevance of B-cell receptor structure and function in chronic lymphocytic leukemia
The B-cell receptor (BCR) is of critical importance for normal B cells and for the majority of B-cell malignancies, especially chronic lymphocytic leukemia (CLL). The two major subsets of CLL are biologically distinct, being derived from B cells at different stages of differentiation and carrying unmutated (U-CLL) or mutated (M-CLL) IGHV genes. U-CLL, which has a poorer prognosis, often has relatively conserved (stereotypic) IGHV-HD-HJ sequences, indicative of interaction with large (super)antigens and similar to those in normal naive innate B cells. Conserved sequences are less evident in M-CLL, in keeping with its postfollicular origin. However, both subsets exhibit features of chronic antigen exposure in tissue sites, with local proliferative events, but also downregulation of surface immunoglobulin M but not surface immunoglobulin D, a characteristic of normal anergic B cells. BCR-mediated anergy can spread to other receptors such as CXCR4. Circulating CLL cells retain a shadow of tissue-based events that can reverse over time, but the overall extent of anergy is greater in M-CLL. Despite this stereotypic variety and more genomic complexity, BCR-mediated responses in vitro appear relatively homogeneous in U-CLL, but M-CLL is more heterogeneous. The differential balance between antigen-induced proliferation or anergy is the likely determinant of clinical behavior and possibly of response to kinase inhibitors.
158-167
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
July 2014
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda K., Forconi, Francesco and Packham, Graham
(2014)
The meaning and relevance of B-cell receptor structure and function in chronic lymphocytic leukemia.
Seminars in Hematology, 51 (3), .
(doi:10.1053/j.seminhematol.2014.05.003).
(PMID:25048780)
Abstract
The B-cell receptor (BCR) is of critical importance for normal B cells and for the majority of B-cell malignancies, especially chronic lymphocytic leukemia (CLL). The two major subsets of CLL are biologically distinct, being derived from B cells at different stages of differentiation and carrying unmutated (U-CLL) or mutated (M-CLL) IGHV genes. U-CLL, which has a poorer prognosis, often has relatively conserved (stereotypic) IGHV-HD-HJ sequences, indicative of interaction with large (super)antigens and similar to those in normal naive innate B cells. Conserved sequences are less evident in M-CLL, in keeping with its postfollicular origin. However, both subsets exhibit features of chronic antigen exposure in tissue sites, with local proliferative events, but also downregulation of surface immunoglobulin M but not surface immunoglobulin D, a characteristic of normal anergic B cells. BCR-mediated anergy can spread to other receptors such as CXCR4. Circulating CLL cells retain a shadow of tissue-based events that can reverse over time, but the overall extent of anergy is greater in M-CLL. Despite this stereotypic variety and more genomic complexity, BCR-mediated responses in vitro appear relatively homogeneous in U-CLL, but M-CLL is more heterogeneous. The differential balance between antigen-induced proliferation or anergy is the likely determinant of clinical behavior and possibly of response to kinase inhibitors.
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e-pub ahead of print date: 15 May 2014
Published date: July 2014
Organisations:
Cancer Sciences
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Local EPrints ID: 385500
URI: http://eprints.soton.ac.uk/id/eprint/385500
ISSN: 0037-1963
PURE UUID: 04fb596e-8039-4371-b960-2aa4e40e88fb
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Date deposited: 20 Jan 2016 11:46
Last modified: 15 Mar 2024 03:41
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