Survival of human lymphoma cells requires B-cell receptor engagement by self-antigens.
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.
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Ryan M
RM
Young
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Tianyi
T
Wu
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Roland
R
Schmitz
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Moez
M
Dawood
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Wenming
W
Xiao
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
James D
JD
Phelan
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Weihong
W
Xu
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511;
Laurence
L
Menard
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511;
Eric
E
Meffre
Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010;
Wing-Chung C
WC
Chan
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Elaine S
ES
Jaffe
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6;
Randy D
RD
Gascoyne
Hematopathology Section, Department of Pathology, Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain;
Elías
E
Campo
Department of Pathology, University of Würzburg, 97080 Würzburg, Germany;
Andreas
A
Rosenwald
Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, 70376 Stuttgart, Germany;
German
G
Ott
Department of Pathology, Oslo University Hospital, 0310 Oslo, Norway;
Jan
J
Delabie
Department of Pathology, University of Arizona, Tucson, AZ 85724.
Lisa M
LM
Rimsza
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; lstaudt@mail.nih.gov.
Louis M
LM
Staudt
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics; D001324:Autoantigens / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D051925:CD79 Antigens / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D034622:RNA Interference; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
D001324:Autoantigens; D051925:CD79 Antigens; D011947:Receptors, Antigen, B-Cell
B-cell receptor; cancer biology; lymphoma