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IL-10 production by CLL cells is enhanced in the anergic IGHV mutated subset and associates with reduced DNA methylation of the IL10 locus

IL-10 production by CLL cells is enhanced in the anergic IGHV mutated subset and associates with reduced DNA methylation of the IL10 locus
IL-10 production by CLL cells is enhanced in the anergic IGHV mutated subset and associates with reduced DNA methylation of the IL10 locus
Chronic lymphocytic leukemias (CLLs) with unmutated (U-CLL) or mutated (M-CLL) IGHV have variable features of immunosuppression, possibly influenced by those CLL cells activated to produce interleukin 10 (IL-10). The two subsets differ in their levels of anergy, defined by low surface immunoglobulin M levels/signaling capacity, and in their DNA methylation profile, particularly variable in M-CLL. We have now found that levels of IL-10 produced by activated CLL cells were highly variable. Levels were higher in M-CLL than in U-CLL and correlated with anergy. DNA methylation analysis of IL10 locus revealed two previously uncharacterized 'variably methylated regions' (CLL-VMRs1/2) in the gene body, but similarly low methylation in the promoter of both U-CLL and M-CLL. CLL-VMR1/2 methylation was lower in M-CLL than in U-CLL and inversely correlated with IL-10 induction. A functional signal transducer and activator of transcription 3 (STAT3) binding site in CLL-VMR2 was confirmed by proximity ligation and luciferase assays, whereas inhibition of SYK-mediated STAT3 activation resulted in suppression of IL10. The data suggest epigenetic control of IL-10 production. Higher tumor load may compensate the reduced IL-10 production in U-CLL, accounting for clinical immunosuppression in both subsets. The observation that SYK inhibition also suppresses IL-10 provides a potential new rationale for therapeutic targeting and immunological rescue by SYK inhibitors in CLL.
0887-6924
1686-1694
Drennan, S.
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D'Avola, A.
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Gao, Y.
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Weigel, C.
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Chrysostomou, E.
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Steele, A.J.
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Zenz, T.
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Plass, C.
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Johnson, P.W.
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Williams, A.P.
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Packham, G.
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Stevenson, F.K.
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Oakes, C.C.
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Forconi, F.
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Drennan, S.
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D'Avola, A.
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Gao, Y.
eea234ba-f566-4f21-a65e-234b84cba285
Weigel, C.
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Chrysostomou, E.
6058d60a-3dc7-4b92-af79-5281a8b75ee3
Steele, A.J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Zenz, T.
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Plass, C.
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Johnson, P.W.
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Williams, A.P.
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Packham, G.
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Stevenson, F.K.
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Oakes, C.C.
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Forconi, F.
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Drennan, S., D'Avola, A., Gao, Y., Weigel, C., Chrysostomou, E., Steele, A.J., Zenz, T., Plass, C., Johnson, P.W., Williams, A.P., Packham, G., Stevenson, F.K., Oakes, C.C. and Forconi, F. (2017) IL-10 production by CLL cells is enhanced in the anergic IGHV mutated subset and associates with reduced DNA methylation of the IL10 locus. Leukemia, 31 (8), 1686-1694. (doi:10.1038/leu.2016.356). (PMID:27890932)

Record type: Article

Abstract

Chronic lymphocytic leukemias (CLLs) with unmutated (U-CLL) or mutated (M-CLL) IGHV have variable features of immunosuppression, possibly influenced by those CLL cells activated to produce interleukin 10 (IL-10). The two subsets differ in their levels of anergy, defined by low surface immunoglobulin M levels/signaling capacity, and in their DNA methylation profile, particularly variable in M-CLL. We have now found that levels of IL-10 produced by activated CLL cells were highly variable. Levels were higher in M-CLL than in U-CLL and correlated with anergy. DNA methylation analysis of IL10 locus revealed two previously uncharacterized 'variably methylated regions' (CLL-VMRs1/2) in the gene body, but similarly low methylation in the promoter of both U-CLL and M-CLL. CLL-VMR1/2 methylation was lower in M-CLL than in U-CLL and inversely correlated with IL-10 induction. A functional signal transducer and activator of transcription 3 (STAT3) binding site in CLL-VMR2 was confirmed by proximity ligation and luciferase assays, whereas inhibition of SYK-mediated STAT3 activation resulted in suppression of IL10. The data suggest epigenetic control of IL-10 production. Higher tumor load may compensate the reduced IL-10 production in U-CLL, accounting for clinical immunosuppression in both subsets. The observation that SYK inhibition also suppresses IL-10 provides a potential new rationale for therapeutic targeting and immunological rescue by SYK inhibitors in CLL.

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Accepted/In Press date: 4 November 2016
e-pub ahead of print date: 28 November 2016
Published date: August 2017
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 404667
URI: http://eprints.soton.ac.uk/id/eprint/404667
ISSN: 0887-6924
PURE UUID: d9d4b422-cb11-4e8c-9df8-356e8e3942e6
ORCID for A.J. Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for P.W. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for G. Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for F.K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021
ORCID for F. Forconi: ORCID iD orcid.org/0000-0002-2211-1831

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Date deposited: 19 Jan 2017 14:51
Last modified: 16 Mar 2024 04:09

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Contributors

Author: S. Drennan
Author: A. D'Avola
Author: Y. Gao
Author: C. Weigel
Author: E. Chrysostomou
Author: A.J. Steele ORCID iD
Author: T. Zenz
Author: C. Plass
Author: P.W. Johnson ORCID iD
Author: A.P. Williams
Author: G. Packham ORCID iD
Author: F.K. Stevenson ORCID iD
Author: C.C. Oakes
Author: F. Forconi ORCID iD

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