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Tumor cells of hairy cell leukemia express multiple clonally related immunoglobulin isotypes via RNA splicing

Tumor cells of hairy cell leukemia express multiple clonally related immunoglobulin isotypes via RNA splicing
Tumor cells of hairy cell leukemia express multiple clonally related immunoglobulin isotypes via RNA splicing
Hairy cell leukemia (HCL) derives from a mature B cell and expresses markers associated with activation. Analysis of immunoglobulin variable region genes has revealed somatic mutation in most cases, consistent with an origin from a cell that has encountered the germinal center. One unusual feature of hairy cells (HCs) is the frequent expression of multiple immunoglobulin heavy chain isotypes, with dominance of immunoglobulin (Ig)-G3, but only a single light chain type. The origin and clonal relationship of these isotype variants have been unclear. In order to probe the isotype switching status of HCL, RNA transcripts of VHDJH- constant region sequences from 5 cases of typical HCL, all expressing multiple surface immunoglobulin isotypes, were analyzed. Tumor VHDJH-Cµ sequences were identified and found to be somatically mutated (range, 1.4% to 6.5%), with a low level of intraclonal heterogeneity. Additional immunoglobulin isotypes of identical VHDJH sequence were also identified, including IgD (5 of 5), IgG3 (5 of 5), IgG1 (3 of 5), IgG2 (2 of 5), IgA1 (4 of 5), and IgA2 (1 of 5). Derivation of multiple isotypes from individual cells was demonstrated by analyzing transcripts in single sorted cells from one patient, with evidence for coexistence of isotype variants in 10 of 10 cells. These findings indicate that clonally related multiple isotypes coexist in single HCs, with individual isotypes presumably generated via RNA splicing. Production of IgG3 appears common, but IgG1, IgG2, IgA1, and IgA2 also arise, indicating a continuing influence of a directed process on the tumor clone. These HCs appear to be arrested at the point of isotype switch, where RNA processing may precede deletional recombination.
0006-4971
1174-1181
Forconi, Francesco
ba40e5ec-24ea-48d5-9a69-c0ffedaf8894
Sahota, Surinder S.
66c1457f-cba2-4c49-9c8c-fcee0748b6b8
Raspadori, Donatella
185f6866-6d10-4f86-9add-72938cea80b3
Mockridge, Christopher I.
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Lauria, Francesco
f01f163b-abcb-4aad-b952-f4356692f519
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Forconi, Francesco
ba40e5ec-24ea-48d5-9a69-c0ffedaf8894
Sahota, Surinder S.
66c1457f-cba2-4c49-9c8c-fcee0748b6b8
Raspadori, Donatella
185f6866-6d10-4f86-9add-72938cea80b3
Mockridge, Christopher I.
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
Lauria, Francesco
f01f163b-abcb-4aad-b952-f4356692f519
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c

Forconi, Francesco, Sahota, Surinder S., Raspadori, Donatella, Mockridge, Christopher I., Lauria, Francesco and Stevenson, Freda K. (2001) Tumor cells of hairy cell leukemia express multiple clonally related immunoglobulin isotypes via RNA splicing. Blood, 98 (4), 1174-1181.

Record type: Article

Abstract

Hairy cell leukemia (HCL) derives from a mature B cell and expresses markers associated with activation. Analysis of immunoglobulin variable region genes has revealed somatic mutation in most cases, consistent with an origin from a cell that has encountered the germinal center. One unusual feature of hairy cells (HCs) is the frequent expression of multiple immunoglobulin heavy chain isotypes, with dominance of immunoglobulin (Ig)-G3, but only a single light chain type. The origin and clonal relationship of these isotype variants have been unclear. In order to probe the isotype switching status of HCL, RNA transcripts of VHDJH- constant region sequences from 5 cases of typical HCL, all expressing multiple surface immunoglobulin isotypes, were analyzed. Tumor VHDJH-Cµ sequences were identified and found to be somatically mutated (range, 1.4% to 6.5%), with a low level of intraclonal heterogeneity. Additional immunoglobulin isotypes of identical VHDJH sequence were also identified, including IgD (5 of 5), IgG3 (5 of 5), IgG1 (3 of 5), IgG2 (2 of 5), IgA1 (4 of 5), and IgA2 (1 of 5). Derivation of multiple isotypes from individual cells was demonstrated by analyzing transcripts in single sorted cells from one patient, with evidence for coexistence of isotype variants in 10 of 10 cells. These findings indicate that clonally related multiple isotypes coexist in single HCs, with individual isotypes presumably generated via RNA splicing. Production of IgG3 appears common, but IgG1, IgG2, IgA1, and IgA2 also arise, indicating a continuing influence of a directed process on the tumor clone. These HCs appear to be arrested at the point of isotype switch, where RNA processing may precede deletional recombination.

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Published date: 2001

Identifiers

Local EPrints ID: 26309
URI: http://eprints.soton.ac.uk/id/eprint/26309
ISSN: 0006-4971
PURE UUID: 66218eb8-c702-4478-8c62-24915a022f73
ORCID for Freda K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

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Date deposited: 24 Apr 2006
Last modified: 23 Jul 2022 01:41

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Contributors

Author: Francesco Forconi
Author: Surinder S. Sahota
Author: Donatella Raspadori
Author: Christopher I. Mockridge
Author: Francesco Lauria

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