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

68 Scopus citations

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

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Keywords

  • B-cell receptor
  • Cancer biology
  • Lymphoma

ASJC Scopus subject areas

  • General

Cite this

Young, R. M., Wu, T., Schmitz, R., Dawood, M., Xiao, W., Phelan, J. D., Xu, W., Menard, L., Meffre, E., Chan, W. C. C., Jaffe, E. S., Gascoyne, R. D., Campo, E., Rosenwald, A., Ott, G., Delabie, J., Rimsza, L. M., & Staudt, L. M. (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, 112(44), 13447-13454. https://doi.org/10.1073/pnas.1514944112