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IgM-expressing Waldenstrom's Macroglobulinemia tumor cells reveal a potential for isotype switch

IgM-expressing Waldenstrom's Macroglobulinemia tumor cells reveal a potential for isotype switch
IgM-expressing Waldenstrom's Macroglobulinemia tumor cells reveal a potential for isotype switch
In Waldenstrom’s macroglobulinemia (WM), which locates primarily in the bone marrow (BM), VH gene analysis had previously suggested origins from a post-follicular B-cell arresting prior to isotype switch. Using more sensitive assays, facilitated by amplified cDNA from BM cells, nested PCR unexpectedly revealed tumor-derived isotype-switch transcripts in 7/7 cases. In 5/7 cases, both C and C variant transcripts were identified, and C or C only in 2/7. Detection of activation induced cytidine deaminase (AID) and germline and circle transcripts confirmed switching activity. Selected gene expression profiles established the memory B-cell marker CD27 as highly expressed in all cases. These findings were evaluated further in additional WM cases where availability of tumor material allowed detailed analysis. In 2/2 cases, phenotype suggested a variable CD27 expression within the tumor clone. In these, tumor IgM transcripts were readily detected in both the CD19+CD27+ and CD19+CD27– fractions, and in 1 of the 2 cases, post-switched tumor-derived C transcripts were also identified in each fraction. In this WM case, the frequency of tumor-derived transcripts was then assessed at the single cell level. Switch transcripts were identified in 3/96 cells with no co-expression of the IgM isotype. Similarly, AID transcripts were observed in some cells, not always correlating with switch events or with ongoing somatic mutation, which was apparent in VDJ-Cµ sequences. These findings reveal a dynamic intratumoral diversification, with AID activated and ongoing mutational and switch activity occurring post-transformation in a proportion of the tumor clone. Heterogeneity in CD27 expression is also evident within tumor cells, revealing phenotypic change. Interestingly, these data indicate that although WM tumor cells have arrested at the IgM stage and do not express isotype switched Ig, they retain the capacity to initiate events critical for isotype switch.
myeloma, cell, tumor-cells, cells, tumor, time
0006-4971
p.292A
Sahota, Surinder S.
66c1457f-cba2-4c49-9c8c-fcee0748b6b8
Babbage, Gavin
d2036377-f36a-4a4a-8634-4b0394dffe28
Townsend, Mark
08e4f0af-4360-402b-a3a3-a96a31f7918d
Mockridge, Ian C.
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Zojer, Niklas
88a51a4d-0b56-4832-bc0f-f102fc49d656
Garand, Richard
ba803747-c0ac-409f-a9c2-b61fde009f8c
Shaughnessy, John
fbc05f87-16c8-43e0-9a44-c42889c5b37a
Sahota, Surinder S.
66c1457f-cba2-4c49-9c8c-fcee0748b6b8
Babbage, Gavin
d2036377-f36a-4a4a-8634-4b0394dffe28
Townsend, Mark
08e4f0af-4360-402b-a3a3-a96a31f7918d
Mockridge, Ian C.
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Zojer, Niklas
88a51a4d-0b56-4832-bc0f-f102fc49d656
Garand, Richard
ba803747-c0ac-409f-a9c2-b61fde009f8c
Shaughnessy, John
fbc05f87-16c8-43e0-9a44-c42889c5b37a

Sahota, Surinder S., Babbage, Gavin, Townsend, Mark, Mockridge, Ian C., Zojer, Niklas, Garand, Richard and Shaughnessy, John (2005) IgM-expressing Waldenstrom's Macroglobulinemia tumor cells reveal a potential for isotype switch. Blood, 106 (11), p.292A.

Record type: Article

Abstract

In Waldenstrom’s macroglobulinemia (WM), which locates primarily in the bone marrow (BM), VH gene analysis had previously suggested origins from a post-follicular B-cell arresting prior to isotype switch. Using more sensitive assays, facilitated by amplified cDNA from BM cells, nested PCR unexpectedly revealed tumor-derived isotype-switch transcripts in 7/7 cases. In 5/7 cases, both C and C variant transcripts were identified, and C or C only in 2/7. Detection of activation induced cytidine deaminase (AID) and germline and circle transcripts confirmed switching activity. Selected gene expression profiles established the memory B-cell marker CD27 as highly expressed in all cases. These findings were evaluated further in additional WM cases where availability of tumor material allowed detailed analysis. In 2/2 cases, phenotype suggested a variable CD27 expression within the tumor clone. In these, tumor IgM transcripts were readily detected in both the CD19+CD27+ and CD19+CD27– fractions, and in 1 of the 2 cases, post-switched tumor-derived C transcripts were also identified in each fraction. In this WM case, the frequency of tumor-derived transcripts was then assessed at the single cell level. Switch transcripts were identified in 3/96 cells with no co-expression of the IgM isotype. Similarly, AID transcripts were observed in some cells, not always correlating with switch events or with ongoing somatic mutation, which was apparent in VDJ-Cµ sequences. These findings reveal a dynamic intratumoral diversification, with AID activated and ongoing mutational and switch activity occurring post-transformation in a proportion of the tumor clone. Heterogeneity in CD27 expression is also evident within tumor cells, revealing phenotypic change. Interestingly, these data indicate that although WM tumor cells have arrested at the IgM stage and do not express isotype switched Ig, they retain the capacity to initiate events critical for isotype switch.

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More information

Published date: 16 November 2005
Additional Information: ASH Annual Meeting Abstracts, Poster Sessions. Abstract 994.
Keywords: myeloma, cell, tumor-cells, cells, tumor, time

Identifiers

Local EPrints ID: 62911
URI: http://eprints.soton.ac.uk/id/eprint/62911
ISSN: 0006-4971
PURE UUID: 2942747f-e010-4727-bf0c-998285ef34f3
ORCID for Richard Garand: ORCID iD orcid.org/0000-0002-0933-5021

Catalogue record

Date deposited: 12 Nov 2008
Last modified: 23 Jul 2022 01:41

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Contributors

Author: Surinder S. Sahota
Author: Gavin Babbage
Author: Mark Townsend
Author: Ian C. Mockridge
Author: Niklas Zojer
Author: Richard Garand ORCID iD
Author: John Shaughnessy

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