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Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL

JA. Eken, MT. Koning, K. Kupcova, JH. Sepúlveda Yáñez, RAL. de Groen, E. Quinten, J. Janssen, CAM. van Bergen, JSP. Vermaat, A. Cleven, MA. Navarrete, B. Ylstra, D. de Jong, O. Havranek, H. Jumaa, H. Veelken

. 2024 ; 221 (5) : . [pub] 20240321

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc24006485

Grant support
10208 KWF Dutch Cancer Society
Agencia Nacional de Investigacion y Desarrollo
2016-72170683 Doctorado Becas Chile
AZV NV18-03-00117 Czech Health Research Council
PRIMUS/17/MED/9 Charles University in Prague
LX22NPO5102 National Institute for Cancer Research
European Union

Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking. Autonomous BCR signaling was associated with IgM isotype, dependent on somatic BCR mutations and individual HCDR3 sequences, and largely restricted to non-GCB DLBCL. Autonomous BCR signaling represents a novel immunological oncogenic driver mechanism in DLBCL originating from individual BCR sequences and adds a new dimension to currently proposed genetics- and transcriptomics-based DLBCL classifications.

References provided by Crossref.org

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$a Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking. Autonomous BCR signaling was associated with IgM isotype, dependent on somatic BCR mutations and individual HCDR3 sequences, and largely restricted to non-GCB DLBCL. Autonomous BCR signaling represents a novel immunological oncogenic driver mechanism in DLBCL originating from individual BCR sequences and adds a new dimension to currently proposed genetics- and transcriptomics-based DLBCL classifications.
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