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Structural and functional features of the B-cell receptor in IgG-positive chronic lymphocytic leukemia

Structural and functional features of the B-cell receptor in IgG-positive chronic lymphocytic leukemia
Structural and functional features of the B-cell receptor in IgG-positive chronic lymphocytic leukemia
PURPOSE: To determine the origin and relationship of the rare IgG+ variant of chronic lymphocytic leukemia (CLL) to the two common IgM+IgD+ subsets that are distinguished by expression of unmutated or mutated V(H) genes, with the former having a worse prognosis. EXPERIMENTAL DESIGN: IgG+ CLL cells were characterized using phenotypic, functional, and immunogenetic analyses. RESULTS: IgG+ CLL was phenotypically similar to mutated IgM+IgD+ CLL (M-CLL) and variably expressed CD38 (4 of 14). ZAP-70, a tyrosine kinase preferentially expressed in unmutated CLL, was found in only 2 of 14 cases. The ability to signal via surface IgM (sIgM) varies between the main subsets of CLL and is associated with expression of ZAP-70. In IgG(+) CLL, 9 of 14 responded to engagement of sIgG with no apparent requirement for expression of CD38 or ZAP-70. However, signal capacity correlated with intensity of sIgG expression. Most switched immunoglobulin variable region genes were somatically mutated without intraclonal variation, and no case expressed activation-induced cytidine deaminase. Derivation from a postgerminal center B cell is, therefore, likely, and a relationship with M-CLL is suggested. This is supported by a shared biased usage of the V4-34 gene. Similar bias in normal B cells developed with age, providing an expanded population for transforming events. However, conserved sequences detected in the CDR3 of V4-34-encoded gamma chains were not found M-CLL, indicating no direct path of isotype switch from M-CLL. CONCLUSION: IgG+ CLL is likely to arise from an age-related expanded pool of B cells, on a path parallel to M-CLL, and perhaps with a similar clinical course.
1078-0432
1672-1679
Potter, Kathleen N.
86a99047-494b-405b-a3f7-650c1dcd5838
Mockridge, C. Ian
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Neville, Louise
d031514f-e527-4fd9-89f3-481103e2634e
Wheatley, Isla
a6564fc5-68c6-476d-a3e4-e86c1be33fc4
Schenk, Michael
7eea4cc1-549b-4161-90d5-0e5b05a298f6
Orchard, Jennifer
0e19209b-25ba-494b-b33e-61ce6fb12e27
Duncombe, Andrew S.
ce7cb7e9-5aec-4801-ab3c-18b4de474fef
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Potter, Kathleen N.
86a99047-494b-405b-a3f7-650c1dcd5838
Mockridge, C. Ian
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Neville, Louise
d031514f-e527-4fd9-89f3-481103e2634e
Wheatley, Isla
a6564fc5-68c6-476d-a3e4-e86c1be33fc4
Schenk, Michael
7eea4cc1-549b-4161-90d5-0e5b05a298f6
Orchard, Jennifer
0e19209b-25ba-494b-b33e-61ce6fb12e27
Duncombe, Andrew S.
ce7cb7e9-5aec-4801-ab3c-18b4de474fef
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c

Potter, Kathleen N., Mockridge, C. Ian, Neville, Louise, Wheatley, Isla, Schenk, Michael, Orchard, Jennifer, Duncombe, Andrew S., Packham, Graham and Stevenson, Freda K. (2006) Structural and functional features of the B-cell receptor in IgG-positive chronic lymphocytic leukemia. Clinical Cancer Research, 12 (6), 1672-1679. (doi:10.1158/1078-0432.CCR-05-2164).

Record type: Article

Abstract

PURPOSE: To determine the origin and relationship of the rare IgG+ variant of chronic lymphocytic leukemia (CLL) to the two common IgM+IgD+ subsets that are distinguished by expression of unmutated or mutated V(H) genes, with the former having a worse prognosis. EXPERIMENTAL DESIGN: IgG+ CLL cells were characterized using phenotypic, functional, and immunogenetic analyses. RESULTS: IgG+ CLL was phenotypically similar to mutated IgM+IgD+ CLL (M-CLL) and variably expressed CD38 (4 of 14). ZAP-70, a tyrosine kinase preferentially expressed in unmutated CLL, was found in only 2 of 14 cases. The ability to signal via surface IgM (sIgM) varies between the main subsets of CLL and is associated with expression of ZAP-70. In IgG(+) CLL, 9 of 14 responded to engagement of sIgG with no apparent requirement for expression of CD38 or ZAP-70. However, signal capacity correlated with intensity of sIgG expression. Most switched immunoglobulin variable region genes were somatically mutated without intraclonal variation, and no case expressed activation-induced cytidine deaminase. Derivation from a postgerminal center B cell is, therefore, likely, and a relationship with M-CLL is suggested. This is supported by a shared biased usage of the V4-34 gene. Similar bias in normal B cells developed with age, providing an expanded population for transforming events. However, conserved sequences detected in the CDR3 of V4-34-encoded gamma chains were not found M-CLL, indicating no direct path of isotype switch from M-CLL. CONCLUSION: IgG+ CLL is likely to arise from an age-related expanded pool of B cells, on a path parallel to M-CLL, and perhaps with a similar clinical course.

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Published date: March 2006

Identifiers

Local EPrints ID: 44619
URI: http://eprints.soton.ac.uk/id/eprint/44619
ISSN: 1078-0432
PURE UUID: f2e067ba-03f8-46bf-a53e-46bf4eff7e59
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: 06 Mar 2007
Last modified: 03 Dec 2019 01:59

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