The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy
The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy
Biologists and clinicians agree that the B-cell receptor influences the behavior of chronic lymphocytic leukemia, and promising new drugs are aimed at receptor-associated kinases. Engagement of surface immunoglobulin by antigen is a key driver of malignant cells with outcome influenced by the nature of the cell, the level of stimulation and the microenvironment. Analysis of surface immunoglobulin-mediated signaling in the two major disease subsets defined by IGHV mutational status reveals bifurcation of responses toward proliferation or anergy. Mutated chronic lymphocytic leukemia, generally of relatively good prognosis, is mainly, but not exclusively, driven towards anergy in vivo. In contrast, unmutated chronic lymphocytic leukemia shows less evidence for anergy in vivo retaining more responsiveness to surface immunoglobulin M-mediated signaling, possibly explaining increased tumor progression. Expression and function of surface immunoglobulin M in unmutated chronic lymphocytic leukemia appear rather homogeneous, but mutated chronic lymphocytic leukemia exhibits a highly heterogeneous profile that may relate to further variable clinical behavior within this subset. Anergy should increase susceptibility to apoptosis but, in leukemic cells, this may be countered by overexpression of the B-cell lymphoma-2 survival protein. Maintained anergy spreads to chemokines and adhesion molecules, restraining homing and migration. However, anergy is not necessarily completely benign, being able to reverse and regenerate surface immunoglobulin M-mediated responses. A two-pronged attack on proliferative and anti-apoptotic pathways may succeed. Increased understanding of how chronic lymphocytic leukemia cells are driven to anergy or proliferation should reveal predictive biomarkers of progression and of likely response to kinase inhibitors, which could assist therapeutic decisions.
1138-1148
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Krysov, Serge
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Allen, Alex
660f61b5-0ccc-46f6-a638-4495d7ae7686
Savelyeva, Natalia
804c3e15-d260-4717-9b7c-15c16ba87fc7
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
July 2014
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Krysov, Serge
2cc89580-a6fb-4d65-837b-163644bbf578
Allen, Alex
660f61b5-0ccc-46f6-a638-4495d7ae7686
Savelyeva, Natalia
804c3e15-d260-4717-9b7c-15c16ba87fc7
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Packham, Graham, Krysov, Serge, Allen, Alex, Savelyeva, Natalia, Steele, Andrew J., Forconi, Francesco and Stevenson, Freda K.
(2014)
The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy.
Haematologica, 99 (7), .
(doi:10.3324/haematol.2013.098384).
(PMID:24986876)
Abstract
Biologists and clinicians agree that the B-cell receptor influences the behavior of chronic lymphocytic leukemia, and promising new drugs are aimed at receptor-associated kinases. Engagement of surface immunoglobulin by antigen is a key driver of malignant cells with outcome influenced by the nature of the cell, the level of stimulation and the microenvironment. Analysis of surface immunoglobulin-mediated signaling in the two major disease subsets defined by IGHV mutational status reveals bifurcation of responses toward proliferation or anergy. Mutated chronic lymphocytic leukemia, generally of relatively good prognosis, is mainly, but not exclusively, driven towards anergy in vivo. In contrast, unmutated chronic lymphocytic leukemia shows less evidence for anergy in vivo retaining more responsiveness to surface immunoglobulin M-mediated signaling, possibly explaining increased tumor progression. Expression and function of surface immunoglobulin M in unmutated chronic lymphocytic leukemia appear rather homogeneous, but mutated chronic lymphocytic leukemia exhibits a highly heterogeneous profile that may relate to further variable clinical behavior within this subset. Anergy should increase susceptibility to apoptosis but, in leukemic cells, this may be countered by overexpression of the B-cell lymphoma-2 survival protein. Maintained anergy spreads to chemokines and adhesion molecules, restraining homing and migration. However, anergy is not necessarily completely benign, being able to reverse and regenerate surface immunoglobulin M-mediated responses. A two-pronged attack on proliferative and anti-apoptotic pathways may succeed. Increased understanding of how chronic lymphocytic leukemia cells are driven to anergy or proliferation should reveal predictive biomarkers of progression and of likely response to kinase inhibitors, which could assist therapeutic decisions.
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Accepted/In Press date: 24 March 2014
Published date: July 2014
Organisations:
Cancer Sciences
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Local EPrints ID: 368398
URI: http://eprints.soton.ac.uk/id/eprint/368398
ISSN: 0390-6078
PURE UUID: bda2a209-99fa-481a-ba3b-e3f6e3cfbc10
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Date deposited: 28 Aug 2014 14:01
Last modified: 15 Mar 2024 03:41
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Author:
Serge Krysov
Author:
Alex Allen
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