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IL-4 enhances expression and function of surface IgM in CLL cells

IL-4 enhances expression and function of surface IgM in CLL cells
IL-4 enhances expression and function of surface IgM in CLL cells
Kinase-inhibitors targeting the B-cell receptor (BCR) are now prominent in the treatment of CLL. We have focused here on IL-4, a cytokine which protects normal and malignant B cells from apoptosis, and increases surface (s)IgM expression on murine splenic B cells. First we have demonstrated that IL-4 treatment increased sIgM expression in vitro on peripheral blood B cells obtained from healthy individuals. In CLL, IL-4 target genes are overexpressed in cells purified from the lymph nodes of patients compared to cells derived from matched blood and bone marrow samples. As for normal B cells, IL-4 increased sIgM expression on CLL cells in vitro, especially in samples expressing unmutated V-genes (U-CLL). IL-4-induced sIgM expression was associated with increased receptor signalling activity, measured by anti-IgM-induced calcium mobilisation, and with increased expression of CD79B mRNA and protein, and the "mature" glycoform of sIgM. Importantly, the ability of the BCR-associated kinase inhibitors idelalisib and ibrutinib, approved for treatment of CLL and other B-cell malignancies, to inhibit anti-IgM-induced signalling was reduced following IL-4 pre-treatment in samples from the majority of patients. In contrast to stimulatory effects on sIgM, IL-4 decreased CXCR4 and CXCR5 expression. Therefore CLL cells, particularly within the progressive U-CLL subset, may harness the ability of IL-4 to promote BCR signalling and B-cell retention within lymph nodes. Effects of IL-4 were mediated via JAK3/STAT6 and we propose a potential role for JAK inhibitors in combination with BCR-kinase inhibitors for the treatment of CLL.
0006-4971
3015-3025
Aguilar-Hernandez, Maria M.
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Blunt, Matthew
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Dobson, Rachel
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Yeomans, Alison
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Thirdborough, Stephen
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Larrayoz, Marta
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Smith, Lindsay
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Linley, Adam
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Strefford, Jonathan C.
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Davies, Andrew
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Johnson, Peter
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Savelyeva, Natalia
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Cragg, Mark
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Forconi, Francesco
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Packham, Graham
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Stevenson, Freda K.
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Steele, Andrew J.
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Aguilar-Hernandez, Maria M.
47458836-2c5f-42e6-bcd5-f27ab7d8236d
Blunt, Matthew
b1109de3-6045-4bc3-bd77-6cf26504697d
Dobson, Rachel
252a7763-afae-4499-84b8-e1d746f6042a
Yeomans, Alison
b47f0dfe-596f-4cef-b4b6-2233b7cdd899
Thirdborough, Stephen
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de
Larrayoz, Marta
952a54b7-c539-4f37-8818-0129e634e999
Smith, Lindsay
1d44c2d0-d5af-411e-b6cd-9b5633f2eb1e
Linley, Adam
10879190-27e3-42a9-a28b-3f8d7724e439
Strefford, Jonathan C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Davies, Andrew
0fe6a40a-10d1-4ade-a7e6-d1dceb2470af
Johnson, Peter
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Savelyeva, Natalia
804c3e15-d260-4717-9b7c-15c16ba87fc7
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Packham, Graham
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Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089

Aguilar-Hernandez, Maria M., Blunt, Matthew, Dobson, Rachel, Yeomans, Alison, Thirdborough, Stephen, Larrayoz, Marta, Smith, Lindsay, Linley, Adam, Strefford, Jonathan C., Davies, Andrew, Johnson, Peter, Savelyeva, Natalia, Cragg, Mark, Forconi, Francesco, Packham, Graham, Stevenson, Freda K. and Steele, Andrew J. (2016) IL-4 enhances expression and function of surface IgM in CLL cells. Blood, 127 (24), 3015-3025. (doi:10.1182/blood-2015-11-682906). (PMID:27002119)

Record type: Article

Abstract

Kinase-inhibitors targeting the B-cell receptor (BCR) are now prominent in the treatment of CLL. We have focused here on IL-4, a cytokine which protects normal and malignant B cells from apoptosis, and increases surface (s)IgM expression on murine splenic B cells. First we have demonstrated that IL-4 treatment increased sIgM expression in vitro on peripheral blood B cells obtained from healthy individuals. In CLL, IL-4 target genes are overexpressed in cells purified from the lymph nodes of patients compared to cells derived from matched blood and bone marrow samples. As for normal B cells, IL-4 increased sIgM expression on CLL cells in vitro, especially in samples expressing unmutated V-genes (U-CLL). IL-4-induced sIgM expression was associated with increased receptor signalling activity, measured by anti-IgM-induced calcium mobilisation, and with increased expression of CD79B mRNA and protein, and the "mature" glycoform of sIgM. Importantly, the ability of the BCR-associated kinase inhibitors idelalisib and ibrutinib, approved for treatment of CLL and other B-cell malignancies, to inhibit anti-IgM-induced signalling was reduced following IL-4 pre-treatment in samples from the majority of patients. In contrast to stimulatory effects on sIgM, IL-4 decreased CXCR4 and CXCR5 expression. Therefore CLL cells, particularly within the progressive U-CLL subset, may harness the ability of IL-4 to promote BCR signalling and B-cell retention within lymph nodes. Effects of IL-4 were mediated via JAK3/STAT6 and we propose a potential role for JAK inhibitors in combination with BCR-kinase inhibitors for the treatment of CLL.

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Accepted/In Press date: 16 March 2016
e-pub ahead of print date: 21 March 2016
Published date: 16 June 2016
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 390484
URI: http://eprints.soton.ac.uk/id/eprint/390484
ISSN: 0006-4971
PURE UUID: 5877316a-8a8d-42c9-ae61-ca1a1dfbf381
ORCID for Matthew Blunt: ORCID iD orcid.org/0000-0003-1099-3985
ORCID for Jonathan C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881
ORCID for Andrew Davies: ORCID iD orcid.org/0000-0002-7517-6938
ORCID for Peter Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831
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
ORCID for Andrew J. Steele: ORCID iD orcid.org/0000-0003-0667-1596

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Date deposited: 04 Apr 2016 09:37
Last modified: 15 Mar 2024 03:46

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Contributors

Author: Maria M. Aguilar-Hernandez
Author: Matthew Blunt ORCID iD
Author: Rachel Dobson
Author: Alison Yeomans
Author: Marta Larrayoz
Author: Lindsay Smith
Author: Adam Linley
Author: Andrew Davies ORCID iD
Author: Peter Johnson ORCID iD
Author: Mark Cragg ORCID iD
Author: Graham Packham ORCID iD

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