Somatic diversification and selection of immunoglobulin heavy and light chain variable region genes in IgG+CD5+ chronic lymphocytic leukemia B cells

Shiori Hashimoto, Mariella Dono, Mariko Wakai, Steven L. Allen, Stuart M. Lichtman, Philip Schulman, Vincent P. Vinciguerra, Manlio Ferrarini, Jack Silver, Nicholas Chiorazzi

Research output: Contribution to journalArticle

114 Citations (Scopus)

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5-expressing B lymphocytes. Most studies have found that these leukemic CD5+ B cells, like their normal counterparts, use immunoglobulin (Ig) variable (V) region genes that exhibit minimal, if any, somatic diversity. These and other observations have suggested that CD5+ B cells may be incapable of generating Ig V gene diversity, and therefore may not be able to develop higher affinity binding sites that could be selected by antigen. However, most of the studies of CLL and normal CD5+ B cells have focused on IgM-producing cells. Since somatic mutations are most often seen in B cells that have undergone an isotype class switch, we analyzed the Ig heavy (H) and light (L) chain variable region genes of seven IgG+CD5+ CLL B cells to determine if somatic diversification and antigen selection had occurred. The data derived provide evidence for skewed use, somatic diversification, and antigenic selection of the Ig V region genes. Nonrandom use of both H and L chain V region genes was manifested by an overrepresentation of V(H)4 and V(κ)I family genes and the underrepresentation of the J(H)4 gene segment. Furthermore, V(H)4 gene use was restricted to only two family members (4.21 and 4.18). In four of the seven cases, the V(H) and V(L) genes displayed ≥5% difference from the most homologous known germline counterparts. Polymerase chain reaction and Southern blot analyses performed in two of these patients demonstrated that their unique V(H) CDR2 and adjacent sequences were not present in their germline DNA. In addition, a significant level of diversity was seen in the rearranged DJ(H) segments and at the V(L)-J(L) junctions of every patient that occurred both at the time of recombination and subsequently. The localization of replacement changes to complementarity determining regions of some patients suggested that antigen selection had occurred. Furthermore, the mutations identified in the V(H) and V(L) genes of each individual patient were strikingly similar, both in number and location. Collectively, the data indicate that a subset of CD5+ CLL B cells can display Ig V region gene mutations. In addition, they are consistent with the notions that in some cases antigen selection of these mutations may have occurred, and that antigen stimulation may be a promoting factor in the evolution of certain CLL clones.

Original languageEnglish
Pages (from-to)1507-1517
Number of pages11
JournalJournal of Experimental Medicine
Volume181
Issue number4
DOIs
Publication statusPublished - Apr 1 1995

Fingerprint

Immunoglobulin Light Chains
Immunoglobulin Heavy Chains
B-Cell Chronic Lymphocytic Leukemia
Immunoglobulin G
Immunoglobulin Variable Region
Genes
B-Lymphocytes
Antigens
Mutation
Complementarity Determining Regions
Immunoglobulin Genes
Southern Blotting
Genetic Recombination
Immunoglobulin M
Immunoglobulins
Clone Cells
Binding Sites

ASJC Scopus subject areas

  • Immunology

Cite this

Somatic diversification and selection of immunoglobulin heavy and light chain variable region genes in IgG+CD5+ chronic lymphocytic leukemia B cells. / Hashimoto, Shiori; Dono, Mariella; Wakai, Mariko; Allen, Steven L.; Lichtman, Stuart M.; Schulman, Philip; Vinciguerra, Vincent P.; Ferrarini, Manlio; Silver, Jack; Chiorazzi, Nicholas.

In: Journal of Experimental Medicine, Vol. 181, No. 4, 01.04.1995, p. 1507-1517.

Research output: Contribution to journalArticle

Hashimoto, S, Dono, M, Wakai, M, Allen, SL, Lichtman, SM, Schulman, P, Vinciguerra, VP, Ferrarini, M, Silver, J & Chiorazzi, N 1995, 'Somatic diversification and selection of immunoglobulin heavy and light chain variable region genes in IgG+CD5+ chronic lymphocytic leukemia B cells', Journal of Experimental Medicine, vol. 181, no. 4, pp. 1507-1517. https://doi.org/10.1084/jem.181.4.1507
Hashimoto, Shiori ; Dono, Mariella ; Wakai, Mariko ; Allen, Steven L. ; Lichtman, Stuart M. ; Schulman, Philip ; Vinciguerra, Vincent P. ; Ferrarini, Manlio ; Silver, Jack ; Chiorazzi, Nicholas. / Somatic diversification and selection of immunoglobulin heavy and light chain variable region genes in IgG+CD5+ chronic lymphocytic leukemia B cells. In: Journal of Experimental Medicine. 1995 ; Vol. 181, No. 4. pp. 1507-1517.
@article{3bd007244e1d49419f89448d93ab0882,
title = "Somatic diversification and selection of immunoglobulin heavy and light chain variable region genes in IgG+CD5+ chronic lymphocytic leukemia B cells",
abstract = "Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5-expressing B lymphocytes. Most studies have found that these leukemic CD5+ B cells, like their normal counterparts, use immunoglobulin (Ig) variable (V) region genes that exhibit minimal, if any, somatic diversity. These and other observations have suggested that CD5+ B cells may be incapable of generating Ig V gene diversity, and therefore may not be able to develop higher affinity binding sites that could be selected by antigen. However, most of the studies of CLL and normal CD5+ B cells have focused on IgM-producing cells. Since somatic mutations are most often seen in B cells that have undergone an isotype class switch, we analyzed the Ig heavy (H) and light (L) chain variable region genes of seven IgG+CD5+ CLL B cells to determine if somatic diversification and antigen selection had occurred. The data derived provide evidence for skewed use, somatic diversification, and antigenic selection of the Ig V region genes. Nonrandom use of both H and L chain V region genes was manifested by an overrepresentation of V(H)4 and V(κ)I family genes and the underrepresentation of the J(H)4 gene segment. Furthermore, V(H)4 gene use was restricted to only two family members (4.21 and 4.18). In four of the seven cases, the V(H) and V(L) genes displayed ≥5{\%} difference from the most homologous known germline counterparts. Polymerase chain reaction and Southern blot analyses performed in two of these patients demonstrated that their unique V(H) CDR2 and adjacent sequences were not present in their germline DNA. In addition, a significant level of diversity was seen in the rearranged DJ(H) segments and at the V(L)-J(L) junctions of every patient that occurred both at the time of recombination and subsequently. The localization of replacement changes to complementarity determining regions of some patients suggested that antigen selection had occurred. Furthermore, the mutations identified in the V(H) and V(L) genes of each individual patient were strikingly similar, both in number and location. Collectively, the data indicate that a subset of CD5+ CLL B cells can display Ig V region gene mutations. In addition, they are consistent with the notions that in some cases antigen selection of these mutations may have occurred, and that antigen stimulation may be a promoting factor in the evolution of certain CLL clones.",
author = "Shiori Hashimoto and Mariella Dono and Mariko Wakai and Allen, {Steven L.} and Lichtman, {Stuart M.} and Philip Schulman and Vinciguerra, {Vincent P.} and Manlio Ferrarini and Jack Silver and Nicholas Chiorazzi",
year = "1995",
month = "4",
day = "1",
doi = "10.1084/jem.181.4.1507",
language = "English",
volume = "181",
pages = "1507--1517",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "4",

}

TY - JOUR

T1 - Somatic diversification and selection of immunoglobulin heavy and light chain variable region genes in IgG+CD5+ chronic lymphocytic leukemia B cells

AU - Hashimoto, Shiori

AU - Dono, Mariella

AU - Wakai, Mariko

AU - Allen, Steven L.

AU - Lichtman, Stuart M.

AU - Schulman, Philip

AU - Vinciguerra, Vincent P.

AU - Ferrarini, Manlio

AU - Silver, Jack

AU - Chiorazzi, Nicholas

PY - 1995/4/1

Y1 - 1995/4/1

N2 - Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5-expressing B lymphocytes. Most studies have found that these leukemic CD5+ B cells, like their normal counterparts, use immunoglobulin (Ig) variable (V) region genes that exhibit minimal, if any, somatic diversity. These and other observations have suggested that CD5+ B cells may be incapable of generating Ig V gene diversity, and therefore may not be able to develop higher affinity binding sites that could be selected by antigen. However, most of the studies of CLL and normal CD5+ B cells have focused on IgM-producing cells. Since somatic mutations are most often seen in B cells that have undergone an isotype class switch, we analyzed the Ig heavy (H) and light (L) chain variable region genes of seven IgG+CD5+ CLL B cells to determine if somatic diversification and antigen selection had occurred. The data derived provide evidence for skewed use, somatic diversification, and antigenic selection of the Ig V region genes. Nonrandom use of both H and L chain V region genes was manifested by an overrepresentation of V(H)4 and V(κ)I family genes and the underrepresentation of the J(H)4 gene segment. Furthermore, V(H)4 gene use was restricted to only two family members (4.21 and 4.18). In four of the seven cases, the V(H) and V(L) genes displayed ≥5% difference from the most homologous known germline counterparts. Polymerase chain reaction and Southern blot analyses performed in two of these patients demonstrated that their unique V(H) CDR2 and adjacent sequences were not present in their germline DNA. In addition, a significant level of diversity was seen in the rearranged DJ(H) segments and at the V(L)-J(L) junctions of every patient that occurred both at the time of recombination and subsequently. The localization of replacement changes to complementarity determining regions of some patients suggested that antigen selection had occurred. Furthermore, the mutations identified in the V(H) and V(L) genes of each individual patient were strikingly similar, both in number and location. Collectively, the data indicate that a subset of CD5+ CLL B cells can display Ig V region gene mutations. In addition, they are consistent with the notions that in some cases antigen selection of these mutations may have occurred, and that antigen stimulation may be a promoting factor in the evolution of certain CLL clones.

AB - Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5-expressing B lymphocytes. Most studies have found that these leukemic CD5+ B cells, like their normal counterparts, use immunoglobulin (Ig) variable (V) region genes that exhibit minimal, if any, somatic diversity. These and other observations have suggested that CD5+ B cells may be incapable of generating Ig V gene diversity, and therefore may not be able to develop higher affinity binding sites that could be selected by antigen. However, most of the studies of CLL and normal CD5+ B cells have focused on IgM-producing cells. Since somatic mutations are most often seen in B cells that have undergone an isotype class switch, we analyzed the Ig heavy (H) and light (L) chain variable region genes of seven IgG+CD5+ CLL B cells to determine if somatic diversification and antigen selection had occurred. The data derived provide evidence for skewed use, somatic diversification, and antigenic selection of the Ig V region genes. Nonrandom use of both H and L chain V region genes was manifested by an overrepresentation of V(H)4 and V(κ)I family genes and the underrepresentation of the J(H)4 gene segment. Furthermore, V(H)4 gene use was restricted to only two family members (4.21 and 4.18). In four of the seven cases, the V(H) and V(L) genes displayed ≥5% difference from the most homologous known germline counterparts. Polymerase chain reaction and Southern blot analyses performed in two of these patients demonstrated that their unique V(H) CDR2 and adjacent sequences were not present in their germline DNA. In addition, a significant level of diversity was seen in the rearranged DJ(H) segments and at the V(L)-J(L) junctions of every patient that occurred both at the time of recombination and subsequently. The localization of replacement changes to complementarity determining regions of some patients suggested that antigen selection had occurred. Furthermore, the mutations identified in the V(H) and V(L) genes of each individual patient were strikingly similar, both in number and location. Collectively, the data indicate that a subset of CD5+ CLL B cells can display Ig V region gene mutations. In addition, they are consistent with the notions that in some cases antigen selection of these mutations may have occurred, and that antigen stimulation may be a promoting factor in the evolution of certain CLL clones.

UR - http://www.scopus.com/inward/record.url?scp=0028945621&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028945621&partnerID=8YFLogxK

U2 - 10.1084/jem.181.4.1507

DO - 10.1084/jem.181.4.1507

M3 - Article

VL - 181

SP - 1507

EP - 1517

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 4

ER -