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Surface IgM expression and function associate with clinical behavior, genetic abnormalities and DNA methylation in CLL

Surface IgM expression and function associate with clinical behavior, genetic abnormalities and DNA methylation in CLL
Surface IgM expression and function associate with clinical behavior, genetic abnormalities and DNA methylation in CLL
Chronic lymphocytic leukemia (CLL) with unmutated (U-CLL) or mutated (M-CLL) IGHV displays different states of anergy, indicated by reduced surface Immunoglobulin M (sIgM) levels and signaling, consequent to chronic (super)antigen exposure. The subsets also differ in the incidence of high-risk genetic aberrations and in DNA methylation profile, preserved from the maturational status of the original cell. We focused on sIgM expression and function, measured as intracellular Ca(2+) mobilization following stimulation, and probed correlations with clinical outcome. The relationship with genetic features and maturation status defined by DNA methylation of an 18-gene panel signature was then investigated. SIgM levels/signaling were higher and less variable in U-CLL than in M-CLL and correlated with disease progression between and within U-CLL and M-CLL. In U-CLL, increased levels/signaling associated with +12, del(17p) or NOTCH1 mutations. In M-CLL, there were fewer genetic lesions, while the methylation maturation status, generally higher than in U-CLL, varied and was increased in cases with lower sIgM levels/signaling. These features revealed heterogeneity in M-CLL and U-CLL with clear clinical correlations. Multivariate analyses with phenotype, genetic lesions, or DNA methylation maturation status identified high sIgM levels as a new potential independent factor for disease progression. Multiple influences on sIgM include the cell of origin, the clonal history of antigen encounter in vivo and genetic damage. This simple marker compiles these different factors into an indicator worthy of further investigations for prediction of clinical behavior, particularly within the heterogeneous M-CLL subset.
0006-4971
816-826
D'Avola, Annalisa
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Drennan, Samantha
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Tracy, Ian
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Henderson, Isla
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Chiecchio, Laura
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Larrayoz, Marta
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Rose-Zerilli, Matthew
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Strefford, Jonathan
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Plass, Christoph
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Johnson, Peter W.
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Steele, Andrew J.
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Packham, Graham
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Stevenson, Freda K.
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Oakes, Christopher C.
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Forconi, Francesco
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D'Avola, Annalisa
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Drennan, Samantha
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Tracy, Ian
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Henderson, Isla
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Chiecchio, Laura
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Larrayoz, Marta
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Rose-Zerilli, Matthew
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Strefford, Jonathan
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Plass, Christoph
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Johnson, Peter W.
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Steele, Andrew J.
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Packham, Graham
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Stevenson, Freda K.
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Oakes, Christopher C.
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Forconi, Francesco
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D'Avola, Annalisa, Drennan, Samantha, Tracy, Ian, Henderson, Isla, Chiecchio, Laura, Larrayoz, Marta, Rose-Zerilli, Matthew, Strefford, Jonathan, Plass, Christoph, Johnson, Peter W., Steele, Andrew J., Packham, Graham, Stevenson, Freda K., Oakes, Christopher C. and Forconi, Francesco (2016) Surface IgM expression and function associate with clinical behavior, genetic abnormalities and DNA methylation in CLL. Blood, 128 (6), 816-826. (doi:10.1182/blood-2016-03-707786). (PMID:27301861)

Record type: Article

Abstract

Chronic lymphocytic leukemia (CLL) with unmutated (U-CLL) or mutated (M-CLL) IGHV displays different states of anergy, indicated by reduced surface Immunoglobulin M (sIgM) levels and signaling, consequent to chronic (super)antigen exposure. The subsets also differ in the incidence of high-risk genetic aberrations and in DNA methylation profile, preserved from the maturational status of the original cell. We focused on sIgM expression and function, measured as intracellular Ca(2+) mobilization following stimulation, and probed correlations with clinical outcome. The relationship with genetic features and maturation status defined by DNA methylation of an 18-gene panel signature was then investigated. SIgM levels/signaling were higher and less variable in U-CLL than in M-CLL and correlated with disease progression between and within U-CLL and M-CLL. In U-CLL, increased levels/signaling associated with +12, del(17p) or NOTCH1 mutations. In M-CLL, there were fewer genetic lesions, while the methylation maturation status, generally higher than in U-CLL, varied and was increased in cases with lower sIgM levels/signaling. These features revealed heterogeneity in M-CLL and U-CLL with clear clinical correlations. Multivariate analyses with phenotype, genetic lesions, or DNA methylation maturation status identified high sIgM levels as a new potential independent factor for disease progression. Multiple influences on sIgM include the cell of origin, the clonal history of antigen encounter in vivo and genetic damage. This simple marker compiles these different factors into an indicator worthy of further investigations for prediction of clinical behavior, particularly within the heterogeneous M-CLL subset.

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Surface IgM expression and function associate with clinical behavior, genetic abnormalities and DNA methylation in CLL.pdf - Accepted Manuscript
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Accepted/In Press date: 6 June 2016
e-pub ahead of print date: 14 June 2016
Published date: 11 August 2016
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 396947
URI: http://eprints.soton.ac.uk/id/eprint/396947
ISSN: 0006-4971
PURE UUID: 3d702eff-88e4-469c-b225-4c41413e2a24
ORCID for Ian Tracy: ORCID iD orcid.org/0000-0003-4624-672X
ORCID for Matthew Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350
ORCID for Jonathan Strefford: ORCID iD orcid.org/0000-0002-0972-2881
ORCID for Peter W. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Andrew J. Steele: ORCID iD orcid.org/0000-0003-0667-1596
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 Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831

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Date deposited: 17 Jun 2016 09:02
Last modified: 15 Mar 2024 05:40

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Contributors

Author: Annalisa D'Avola
Author: Samantha Drennan
Author: Ian Tracy ORCID iD
Author: Isla Henderson
Author: Laura Chiecchio
Author: Marta Larrayoz
Author: Christoph Plass
Author: Graham Packham ORCID iD
Author: Christopher C. Oakes

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