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Identification in CLL of circulating intraclonal subgroups with varying B-cell receptor expression and function

Identification in CLL of circulating intraclonal subgroups with varying B-cell receptor expression and function
Identification in CLL of circulating intraclonal subgroups with varying B-cell receptor expression and function
Chronic lymphocytic leukemia (CLL) is a tumor of circulating B cells, variably stimulated and anergized following exposure to antigen in lymphoid tissues. Downmodulation of surface IgM (sIgM) occurs but expression and signal capacity can recover in vitro, and apparently in vivo during recirculation. We have now dissected individual circulating clones of CLL cases according to sIgM expression level by differential binding to bead-bound anti-IgM. Four clear subgroups (SG1-4) with increasing sIgM were identified in 37/37 cases. Engagement of sIgM induced phosphorylation of PLC?2 and ERK1/2 at levels ranging from very low in SG1 to high in SG4. Phosphorylation was suppressed by the BTK inhibitor ibrutinib. Expression of CXCR4 also increased from SG1 to SG4 but markers of previous activation and proliferation were dominant in SG1. Incubation of whole CLL populations in vitro led to striking increases in CXCR4 expression, as well as recovery of sIgM. Clonal analysis reveals dynamic SGs following presumed antigen stimulation in tissues. SG4 represents a fully recovered, potentially dangerous population equipped to migrate to tissue and to receive a proliferative stimulus. SG1 likely represents a post-mitotic unresponsive "resting" population. The effect of ibrutinib on the small SG4 population may be the critical factor in therapeutic success.
0006-4971
2664-2672
Coelho, Vânia
b4a0fbb4-6eb4-4122-900c-f27cc5ebe150
Krysov, Sergey
3a78eac1-af40-4b37-8576-3462947649be
Steele, Andrew
4349f6aa-2e3a-49a8-be73-7716056ae089
Sanchez-Hidalgo, Marina
e2d4dfea-ff48-4423-b14e-9c600bd7895a
Johnson, Peter W.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Chana, Prabhjoat S.
d8689793-7617-45b9-a846-33ae65c9c13d
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Coelho, Vânia
b4a0fbb4-6eb4-4122-900c-f27cc5ebe150
Krysov, Sergey
3a78eac1-af40-4b37-8576-3462947649be
Steele, Andrew
4349f6aa-2e3a-49a8-be73-7716056ae089
Sanchez-Hidalgo, Marina
e2d4dfea-ff48-4423-b14e-9c600bd7895a
Johnson, Peter W.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Chana, Prabhjoat S.
d8689793-7617-45b9-a846-33ae65c9c13d
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8

Coelho, Vânia, Krysov, Sergey, Steele, Andrew, Sanchez-Hidalgo, Marina, Johnson, Peter W., Chana, Prabhjoat S., Packham, Graham, Stevenson, Freda K. and Forconi, Francesco (2013) Identification in CLL of circulating intraclonal subgroups with varying B-cell receptor expression and function. Blood, 122 (15), 2664-2672. (doi:10.1182/blood-2013-02-485425). (PMID:23954894)

Record type: Article

Abstract

Chronic lymphocytic leukemia (CLL) is a tumor of circulating B cells, variably stimulated and anergized following exposure to antigen in lymphoid tissues. Downmodulation of surface IgM (sIgM) occurs but expression and signal capacity can recover in vitro, and apparently in vivo during recirculation. We have now dissected individual circulating clones of CLL cases according to sIgM expression level by differential binding to bead-bound anti-IgM. Four clear subgroups (SG1-4) with increasing sIgM were identified in 37/37 cases. Engagement of sIgM induced phosphorylation of PLC?2 and ERK1/2 at levels ranging from very low in SG1 to high in SG4. Phosphorylation was suppressed by the BTK inhibitor ibrutinib. Expression of CXCR4 also increased from SG1 to SG4 but markers of previous activation and proliferation were dominant in SG1. Incubation of whole CLL populations in vitro led to striking increases in CXCR4 expression, as well as recovery of sIgM. Clonal analysis reveals dynamic SGs following presumed antigen stimulation in tissues. SG4 represents a fully recovered, potentially dangerous population equipped to migrate to tissue and to receive a proliferative stimulus. SG1 likely represents a post-mitotic unresponsive "resting" population. The effect of ibrutinib on the small SG4 population may be the critical factor in therapeutic success.

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e-pub ahead of print date: 16 August 2013
Organisations: Cancer Sciences

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Local EPrints ID: 356097
URI: http://eprints.soton.ac.uk/id/eprint/356097
ISSN: 0006-4971
PURE UUID: 7082484e-9f50-4d60-9cf9-5c06ed9f985f
ORCID for Andrew Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for Peter W. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
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: 06 Sep 2013 10:13
Last modified: 15 Mar 2024 03:40

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Contributors

Author: Vânia Coelho
Author: Sergey Krysov
Author: Andrew Steele ORCID iD
Author: Marina Sanchez-Hidalgo
Author: Prabhjoat S. Chana
Author: Graham Packham ORCID iD

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