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
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
16 November 2005
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), .
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.
This record has no associated files available for download.
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
Catalogue record
Date deposited: 12 Nov 2008
Last modified: 23 Jul 2022 01:41
Export record
Contributors
Author:
Surinder S. Sahota
Author:
Gavin Babbage
Author:
Mark Townsend
Author:
Ian C. Mockridge
Author:
Niklas Zojer
Author:
John Shaughnessy
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics