Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

Ryan M. Young, Tianyi Wu, Roland Schmitz, Moez Dawood, Wenming Xiao, James D. Phelan, Weihong Xu, Laurence Menard, Eric Meffre, Wing Chung C Chan, Elaine S. Jaffe, Randy D. Gascoyne, Elías Campo, Andreas Rosenwald, German Ott, Jan Delabie, Lisa M Rimsza, Louis M. Staudt

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) relies on chronic active B-cell receptor (BCR) signaling. BCR pathway inhibitors induce remissions in a subset of ABC DLBCL patients. BCR microclusters on the surface of ABC cells resemble those generated following antigen engagement of normal B cells. We speculated that binding of lymphoma BCRs to self-antigens initiates and maintains chronic active BCR signaling in ABC DLBCL. To assess whether antigenic engagement of the BCR is required for the ongoing survival of ABC cells, we developed isogenic ABC cells that differed solely with respect to the IgH V region of their BCRs. In competitive assays with wild-type cells, substitution of a heterologous V region impaired the survival of three ABC lines. The viability of one VH4-34+ ABC line and the ability of its BCR to bind to its own cell surface depended on V region residues that mediate the intrinsic autoreactivity of VH4-34 to self-glycoproteins. The BCR of another ABC line reacted with self-antigens in apoptotic debris, and the survival of a third ABC line was sustained by reactivity of its BCR to an idiotypic epitope in its own V region. Hence, a diverse set of self-antigens is responsible for maintaining the malignant survival of ABC DLBCL cells. IgH V regions used by the BCRs of ABC DLBCL biopsy samples varied in their ability to sustain survival of these ABC lines, suggesting a screening procedure to identify patients who might benefit from BCR pathway inhibition.

Original languageEnglish (US)
Pages (from-to)13447-13454
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number44
DOIs
StatePublished - Nov 3 2015

Fingerprint

Autoantigens
Lymphoma
B-Lymphocytes
Survival
Lymphoma, Large B-Cell, Diffuse
Cell Line
B-Lymphocyte Subsets

Keywords

  • B-cell receptor
  • Cancer biology
  • Lymphoma

ASJC Scopus subject areas

  • General

Cite this

Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens. / Young, Ryan M.; Wu, Tianyi; Schmitz, Roland; Dawood, Moez; Xiao, Wenming; Phelan, James D.; Xu, Weihong; Menard, Laurence; Meffre, Eric; Chan, Wing Chung C; Jaffe, Elaine S.; Gascoyne, Randy D.; Campo, Elías; Rosenwald, Andreas; Ott, German; Delabie, Jan; Rimsza, Lisa M; Staudt, Louis M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 44, 03.11.2015, p. 13447-13454.

Research output: Contribution to journalArticle

Young, RM, Wu, T, Schmitz, R, Dawood, M, Xiao, W, Phelan, JD, Xu, W, Menard, L, Meffre, E, Chan, WCC, Jaffe, ES, Gascoyne, RD, Campo, E, Rosenwald, A, Ott, G, Delabie, J, Rimsza, LM & Staudt, LM 2015, 'Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 44, pp. 13447-13454. https://doi.org/10.1073/pnas.1514944112
Young, Ryan M. ; Wu, Tianyi ; Schmitz, Roland ; Dawood, Moez ; Xiao, Wenming ; Phelan, James D. ; Xu, Weihong ; Menard, Laurence ; Meffre, Eric ; Chan, Wing Chung C ; Jaffe, Elaine S. ; Gascoyne, Randy D. ; Campo, Elías ; Rosenwald, Andreas ; Ott, German ; Delabie, Jan ; Rimsza, Lisa M ; Staudt, Louis M. / Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 44. pp. 13447-13454.
@article{9d19fe2c7f134f51aad60dd845068cf4,
title = "Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens",
abstract = "The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) relies on chronic active B-cell receptor (BCR) signaling. BCR pathway inhibitors induce remissions in a subset of ABC DLBCL patients. BCR microclusters on the surface of ABC cells resemble those generated following antigen engagement of normal B cells. We speculated that binding of lymphoma BCRs to self-antigens initiates and maintains chronic active BCR signaling in ABC DLBCL. To assess whether antigenic engagement of the BCR is required for the ongoing survival of ABC cells, we developed isogenic ABC cells that differed solely with respect to the IgH V region of their BCRs. In competitive assays with wild-type cells, substitution of a heterologous V region impaired the survival of three ABC lines. The viability of one VH4-34+ ABC line and the ability of its BCR to bind to its own cell surface depended on V region residues that mediate the intrinsic autoreactivity of VH4-34 to self-glycoproteins. The BCR of another ABC line reacted with self-antigens in apoptotic debris, and the survival of a third ABC line was sustained by reactivity of its BCR to an idiotypic epitope in its own V region. Hence, a diverse set of self-antigens is responsible for maintaining the malignant survival of ABC DLBCL cells. IgH V regions used by the BCRs of ABC DLBCL biopsy samples varied in their ability to sustain survival of these ABC lines, suggesting a screening procedure to identify patients who might benefit from BCR pathway inhibition.",
keywords = "B-cell receptor, Cancer biology, Lymphoma",
author = "Young, {Ryan M.} and Tianyi Wu and Roland Schmitz and Moez Dawood and Wenming Xiao and Phelan, {James D.} and Weihong Xu and Laurence Menard and Eric Meffre and Chan, {Wing Chung C} and Jaffe, {Elaine S.} and Gascoyne, {Randy D.} and El{\'i}as Campo and Andreas Rosenwald and German Ott and Jan Delabie and Rimsza, {Lisa M} and Staudt, {Louis M.}",
year = "2015",
month = "11",
day = "3",
doi = "10.1073/pnas.1514944112",
language = "English (US)",
volume = "112",
pages = "13447--13454",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "44",

}

TY - JOUR

T1 - Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens

AU - Young, Ryan M.

AU - Wu, Tianyi

AU - Schmitz, Roland

AU - Dawood, Moez

AU - Xiao, Wenming

AU - Phelan, James D.

AU - Xu, Weihong

AU - Menard, Laurence

AU - Meffre, Eric

AU - Chan, Wing Chung C

AU - Jaffe, Elaine S.

AU - Gascoyne, Randy D.

AU - Campo, Elías

AU - Rosenwald, Andreas

AU - Ott, German

AU - Delabie, Jan

AU - Rimsza, Lisa M

AU - Staudt, Louis M.

PY - 2015/11/3

Y1 - 2015/11/3

N2 - The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) relies on chronic active B-cell receptor (BCR) signaling. BCR pathway inhibitors induce remissions in a subset of ABC DLBCL patients. BCR microclusters on the surface of ABC cells resemble those generated following antigen engagement of normal B cells. We speculated that binding of lymphoma BCRs to self-antigens initiates and maintains chronic active BCR signaling in ABC DLBCL. To assess whether antigenic engagement of the BCR is required for the ongoing survival of ABC cells, we developed isogenic ABC cells that differed solely with respect to the IgH V region of their BCRs. In competitive assays with wild-type cells, substitution of a heterologous V region impaired the survival of three ABC lines. The viability of one VH4-34+ ABC line and the ability of its BCR to bind to its own cell surface depended on V region residues that mediate the intrinsic autoreactivity of VH4-34 to self-glycoproteins. The BCR of another ABC line reacted with self-antigens in apoptotic debris, and the survival of a third ABC line was sustained by reactivity of its BCR to an idiotypic epitope in its own V region. Hence, a diverse set of self-antigens is responsible for maintaining the malignant survival of ABC DLBCL cells. IgH V regions used by the BCRs of ABC DLBCL biopsy samples varied in their ability to sustain survival of these ABC lines, suggesting a screening procedure to identify patients who might benefit from BCR pathway inhibition.

AB - The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) relies on chronic active B-cell receptor (BCR) signaling. BCR pathway inhibitors induce remissions in a subset of ABC DLBCL patients. BCR microclusters on the surface of ABC cells resemble those generated following antigen engagement of normal B cells. We speculated that binding of lymphoma BCRs to self-antigens initiates and maintains chronic active BCR signaling in ABC DLBCL. To assess whether antigenic engagement of the BCR is required for the ongoing survival of ABC cells, we developed isogenic ABC cells that differed solely with respect to the IgH V region of their BCRs. In competitive assays with wild-type cells, substitution of a heterologous V region impaired the survival of three ABC lines. The viability of one VH4-34+ ABC line and the ability of its BCR to bind to its own cell surface depended on V region residues that mediate the intrinsic autoreactivity of VH4-34 to self-glycoproteins. The BCR of another ABC line reacted with self-antigens in apoptotic debris, and the survival of a third ABC line was sustained by reactivity of its BCR to an idiotypic epitope in its own V region. Hence, a diverse set of self-antigens is responsible for maintaining the malignant survival of ABC DLBCL cells. IgH V regions used by the BCRs of ABC DLBCL biopsy samples varied in their ability to sustain survival of these ABC lines, suggesting a screening procedure to identify patients who might benefit from BCR pathway inhibition.

KW - B-cell receptor

KW - Cancer biology

KW - Lymphoma

UR - http://www.scopus.com/inward/record.url?scp=84946616221&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84946616221&partnerID=8YFLogxK

U2 - 10.1073/pnas.1514944112

DO - 10.1073/pnas.1514944112

M3 - Article

VL - 112

SP - 13447

EP - 13454

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 44

ER -