Variant B cell receptor isotype functions differ in hairy cell leukemia with mutated BRAF and IGHV genes
Variant B cell receptor isotype functions differ in hairy cell leukemia with mutated BRAF and IGHV genes
A functional B-cell receptor (BCR) is critical for survival of normal B-cells, but whether it plays a comparable role in B-cell malignancy is as yet not fully delineated. Typical Hairy Cell Leukemia (HCL) is a rare B-cell tumor, and unique in expressing multiple surface immunoglobulin (sIg) isotypes on individual tumor cells (mult-HCL), to raise questions as to their functional relevance. Typical mult-HCL also displays a mutated BRAF V(600)E lesion. Since wild type BRAF is a primary conduit for transducing normal BCR signals, as revealed by deletion modelling studies, it is as yet not apparent if mutated BRAF alters BCR signal transduction in mult-HCL. To address these questions, we examined BCR signalling in mult-HCL cases uniformly displaying mutated BRAF and IGHV genes. Two apparent functional sets were delineated by IgD co-expression. In sIgD(+ve) mult-HCL, IgD mediated persistent Ca(2+) flux, also evident via >1 sIgH isotype, linked to increased ERK activation and BCR endocytosis. In sIgD(-ve) mult-HCL however, BCR-mediated signals and downstream effects were restricted to a single sIgH isotype, with sIgM notably dysfunctional and remaining immobilised on the cell surface. These observations reveal discordance between expression and function of individual isotypes in mult-HCL. In dual sIgL expressing cases, only a single sIgL was fully functional. We examined effects of anti-BCR stimuli on mult-HCL survival ex-vivo. Significantly, all functional non-IgD isotypes increased ERK1/2 phosphorylation but triggered apoptosis of tumor cells, in both subsets. IgD stimuli, in marked contrast retained tumor viability. Despite mutant BRAF, BCR signals augment ERK1/2 phosphorylation, but isotype dictates functional downstream outcomes. In mult-HCL, sIgD retains a potential to transduce BCR signals for tumor survival in-vivo. The BCR in mult-HCL emerges as subject to complex regulation, with apparent conflicting signalling by individual isotypes when co-expressed with sIgD. This suggests the possibility that mutant BRAF by-passes BCR constraints in mult-HCL.
e86556
Weston-Bell, Nicola J.
c99c8c28-519f-4c3e-bd8c-679995a0472e
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Kluin-Nelemans, Hanneke C.
243d2cac-e859-4b13-94cb-382f0f3e19a7
Sahota, Surinder S.
66c1457f-cba2-4c49-9c8c-fcee0748b6b8
30 January 2014
Weston-Bell, Nicola J.
c99c8c28-519f-4c3e-bd8c-679995a0472e
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Kluin-Nelemans, Hanneke C.
243d2cac-e859-4b13-94cb-382f0f3e19a7
Sahota, Surinder S.
66c1457f-cba2-4c49-9c8c-fcee0748b6b8
Weston-Bell, Nicola J., Forconi, Francesco, Kluin-Nelemans, Hanneke C. and Sahota, Surinder S.
(2014)
Variant B cell receptor isotype functions differ in hairy cell leukemia with mutated BRAF and IGHV genes.
PLoS ONE, 9 (1), .
(doi:10.1371/journal.pone.0086556).
(PMID:24497953)
Abstract
A functional B-cell receptor (BCR) is critical for survival of normal B-cells, but whether it plays a comparable role in B-cell malignancy is as yet not fully delineated. Typical Hairy Cell Leukemia (HCL) is a rare B-cell tumor, and unique in expressing multiple surface immunoglobulin (sIg) isotypes on individual tumor cells (mult-HCL), to raise questions as to their functional relevance. Typical mult-HCL also displays a mutated BRAF V(600)E lesion. Since wild type BRAF is a primary conduit for transducing normal BCR signals, as revealed by deletion modelling studies, it is as yet not apparent if mutated BRAF alters BCR signal transduction in mult-HCL. To address these questions, we examined BCR signalling in mult-HCL cases uniformly displaying mutated BRAF and IGHV genes. Two apparent functional sets were delineated by IgD co-expression. In sIgD(+ve) mult-HCL, IgD mediated persistent Ca(2+) flux, also evident via >1 sIgH isotype, linked to increased ERK activation and BCR endocytosis. In sIgD(-ve) mult-HCL however, BCR-mediated signals and downstream effects were restricted to a single sIgH isotype, with sIgM notably dysfunctional and remaining immobilised on the cell surface. These observations reveal discordance between expression and function of individual isotypes in mult-HCL. In dual sIgL expressing cases, only a single sIgL was fully functional. We examined effects of anti-BCR stimuli on mult-HCL survival ex-vivo. Significantly, all functional non-IgD isotypes increased ERK1/2 phosphorylation but triggered apoptosis of tumor cells, in both subsets. IgD stimuli, in marked contrast retained tumor viability. Despite mutant BRAF, BCR signals augment ERK1/2 phosphorylation, but isotype dictates functional downstream outcomes. In mult-HCL, sIgD retains a potential to transduce BCR signals for tumor survival in-vivo. The BCR in mult-HCL emerges as subject to complex regulation, with apparent conflicting signalling by individual isotypes when co-expressed with sIgD. This suggests the possibility that mutant BRAF by-passes BCR constraints in mult-HCL.
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Accepted/In Press date: 17 December 2013
e-pub ahead of print date: 30 January 2014
Published date: 30 January 2014
Organisations:
Cancer Sciences
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Local EPrints ID: 376785
URI: http://eprints.soton.ac.uk/id/eprint/376785
ISSN: 1932-6203
PURE UUID: c9015123-d9cd-42cb-9082-77700f52181c
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Date deposited: 14 May 2015 11:01
Last modified: 15 Mar 2024 03:41
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Author:
Nicola J. Weston-Bell
Author:
Hanneke C. Kluin-Nelemans
Author:
Surinder S. Sahota
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