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Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status

Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status
Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status
The 2 subsets of chronic lymphocytic leukemia (CLL), of worse or better prognosis, likely derive from pre-GC unmutated B cells, or post-GC mutated B cells, respectively. Different clinical behavior could relate to the ability of tumor cells to respond to surface (slg)-mediated signals. Unmutated cases (U-CLL) have an increased ability to phosphorylate p72(Syk) in response to slgM ligation compared to mutated cases (M-CLL). We now confirm and further investigate this differential signaling in a large cohort by [Ca2+], mobilization. Cases responding to slgM ligation express higher levels of CD38, ZAP-70, and slgM. However, CD38 does not influence signaling in vitro or associate with response in bimodal CD38-expressing cases. Similarly, ZAP-70 expression is not required for response in either U-CLL or M-CLL. Strikingly, partially or completely anergized slgM responses from each subset can recover both slgM expression and signal capacity spontaneously in vitro or following capping/enclocytosis. This provides direct evidence for engagement of putative antigen in vivo. Signaling via slgD differs markedly being almost universally positive in both U-CLL and M-CLL, with no association with CD38 or ZAP-70 expression. Downstream signaling pathways, therefore, appear intact in CLL, locating anergy to slgM, mainly in M-CLL. Integration of differential isotype-specific effects mediated by (auto)antigen may determine tumor behavior.
pathway, immunoglobulin, b cell, tyrosine kinase, tumor-cells, cell, surface, zap-70 expression, pathways, cohort, chronic lymphocytic-leukemia, activation, time, responses, expression, b-cell-receptor, prognosis, leukemia, antigen, in-vitro, lymphocytic-leukemia, cross-linking, antigen receptor, cd38 expression, tumor, cll, cd38, cells, b-cells, vivo, in-vivo, zap-70, surface igm
0006-4971
4424-4431
Mockridge, C. Ian
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Potter, Kathleen N.
86a99047-494b-405b-a3f7-650c1dcd5838
Wheatley, Isla
a6564fc5-68c6-476d-a3e4-e86c1be33fc4
Neville, Louise A.
90a105f3-2ccb-4cd9-9655-68bc96189ac0
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Mockridge, C. Ian
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Potter, Kathleen N.
86a99047-494b-405b-a3f7-650c1dcd5838
Wheatley, Isla
a6564fc5-68c6-476d-a3e4-e86c1be33fc4
Neville, Louise A.
90a105f3-2ccb-4cd9-9655-68bc96189ac0
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c

Mockridge, C. Ian, Potter, Kathleen N., Wheatley, Isla, Neville, Louise A., Packham, Graham and Stevenson, Freda K. (2007) Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status. Blood, 109 (10), 4424-4431. (doi:10.1182/blood-2006-11-056648).

Record type: Article

Abstract

The 2 subsets of chronic lymphocytic leukemia (CLL), of worse or better prognosis, likely derive from pre-GC unmutated B cells, or post-GC mutated B cells, respectively. Different clinical behavior could relate to the ability of tumor cells to respond to surface (slg)-mediated signals. Unmutated cases (U-CLL) have an increased ability to phosphorylate p72(Syk) in response to slgM ligation compared to mutated cases (M-CLL). We now confirm and further investigate this differential signaling in a large cohort by [Ca2+], mobilization. Cases responding to slgM ligation express higher levels of CD38, ZAP-70, and slgM. However, CD38 does not influence signaling in vitro or associate with response in bimodal CD38-expressing cases. Similarly, ZAP-70 expression is not required for response in either U-CLL or M-CLL. Strikingly, partially or completely anergized slgM responses from each subset can recover both slgM expression and signal capacity spontaneously in vitro or following capping/enclocytosis. This provides direct evidence for engagement of putative antigen in vivo. Signaling via slgD differs markedly being almost universally positive in both U-CLL and M-CLL, with no association with CD38 or ZAP-70 expression. Downstream signaling pathways, therefore, appear intact in CLL, locating anergy to slgM, mainly in M-CLL. Integration of differential isotype-specific effects mediated by (auto)antigen may determine tumor behavior.

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More information

Published date: 15 May 2007
Keywords: pathway, immunoglobulin, b cell, tyrosine kinase, tumor-cells, cell, surface, zap-70 expression, pathways, cohort, chronic lymphocytic-leukemia, activation, time, responses, expression, b-cell-receptor, prognosis, leukemia, antigen, in-vitro, lymphocytic-leukemia, cross-linking, antigen receptor, cd38 expression, tumor, cll, cd38, cells, b-cells, vivo, in-vivo, zap-70, surface igm

Identifiers

Local EPrints ID: 44620
URI: http://eprints.soton.ac.uk/id/eprint/44620
ISSN: 0006-4971
PURE UUID: dcb5bfd1-91ed-4999-b010-444db4a6a8cc
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Freda K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

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Date deposited: 02 Mar 2007
Last modified: 16 Mar 2024 03:14

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Contributors

Author: C. Ian Mockridge
Author: Isla Wheatley
Author: Louise A. Neville
Author: Graham Packham ORCID iD

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