Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma

R. Eric Davis, Vu N. Ngo, Georg Lenz, Pavel Tolar, Ryan M. Young, Paul B. Romesser, Holger Kohlhammer, Laurence Lamy, Hong Zhao, Yandan Yang, Weihong Xu, Arthur L. Shaffer, George Wright, Wenming Xiao, John Powell, Jian Kang Jiang, Craig J. Thomas, Andreas Rosenwald, German Ott, Hans Konrad Muller-HermelinkRandy D. Gascoyne, Joseph M. Connors, Nathalie A. Johnson, Lisa M Rimsza, Elias Campo, Elaine S. Jaffe, Wyndham H. Wilson, Jan Delabie, Erlend B. Smeland, Richard I. Fisher, Rita M. Braziel, Raymond R. Tubbs, J. R. Cook, Dennis D. Weisenburger, Wing C. Chan, Susan K. Pierce, Louis M. Staudt

Research output: Contribution to journalArticle

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Abstract

A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD11 is required for constitutive NF-B pathway activity and survival in ABC DLBCL. Roughly 10% of ABC DLBCLs have mutant CARD11 isoforms that activate NF-B, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig-, CD79A and CD79B) killed ABC DLBCLs with wild-type CARD11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)88-92
Number of pages5
JournalNature
Volume463
Issue number7277
DOIs
StatePublished - Jan 7 2010

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Lymphoma, Large B-Cell, Diffuse
B-Lymphocytes
Immunoreceptor Tyrosine-Based Activation Motif
Lymphoma
Marginal Zone B-Cell Lymphoma
Immunoglobulin Subunits
Immunoglobulin Genes
Mutation
Burkitt Lymphoma
Survival
Human Engineering
Genetic Models
Cell Surface Receptors

ASJC Scopus subject areas

  • General

Cite this

Davis, R. E., Ngo, V. N., Lenz, G., Tolar, P., Young, R. M., Romesser, P. B., ... Staudt, L. M. (2010). Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature, 463(7277), 88-92. https://doi.org/10.1038/nature08638

Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. / Davis, R. Eric; Ngo, Vu N.; Lenz, Georg; Tolar, Pavel; Young, Ryan M.; Romesser, Paul B.; Kohlhammer, Holger; Lamy, Laurence; Zhao, Hong; Yang, Yandan; Xu, Weihong; Shaffer, Arthur L.; Wright, George; Xiao, Wenming; Powell, John; Jiang, Jian Kang; Thomas, Craig J.; Rosenwald, Andreas; Ott, German; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D.; Connors, Joseph M.; Johnson, Nathalie A.; Rimsza, Lisa M; Campo, Elias; Jaffe, Elaine S.; Wilson, Wyndham H.; Delabie, Jan; Smeland, Erlend B.; Fisher, Richard I.; Braziel, Rita M.; Tubbs, Raymond R.; Cook, J. R.; Weisenburger, Dennis D.; Chan, Wing C.; Pierce, Susan K.; Staudt, Louis M.

In: Nature, Vol. 463, No. 7277, 07.01.2010, p. 88-92.

Research output: Contribution to journalArticle

Davis, RE, Ngo, VN, Lenz, G, Tolar, P, Young, RM, Romesser, PB, Kohlhammer, H, Lamy, L, Zhao, H, Yang, Y, Xu, W, Shaffer, AL, Wright, G, Xiao, W, Powell, J, Jiang, JK, Thomas, CJ, Rosenwald, A, Ott, G, Muller-Hermelink, HK, Gascoyne, RD, Connors, JM, Johnson, NA, Rimsza, LM, Campo, E, Jaffe, ES, Wilson, WH, Delabie, J, Smeland, EB, Fisher, RI, Braziel, RM, Tubbs, RR, Cook, JR, Weisenburger, DD, Chan, WC, Pierce, SK & Staudt, LM 2010, 'Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma', Nature, vol. 463, no. 7277, pp. 88-92. https://doi.org/10.1038/nature08638
Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010 Jan 7;463(7277):88-92. https://doi.org/10.1038/nature08638
Davis, R. Eric ; Ngo, Vu N. ; Lenz, Georg ; Tolar, Pavel ; Young, Ryan M. ; Romesser, Paul B. ; Kohlhammer, Holger ; Lamy, Laurence ; Zhao, Hong ; Yang, Yandan ; Xu, Weihong ; Shaffer, Arthur L. ; Wright, George ; Xiao, Wenming ; Powell, John ; Jiang, Jian Kang ; Thomas, Craig J. ; Rosenwald, Andreas ; Ott, German ; Muller-Hermelink, Hans Konrad ; Gascoyne, Randy D. ; Connors, Joseph M. ; Johnson, Nathalie A. ; Rimsza, Lisa M ; Campo, Elias ; Jaffe, Elaine S. ; Wilson, Wyndham H. ; Delabie, Jan ; Smeland, Erlend B. ; Fisher, Richard I. ; Braziel, Rita M. ; Tubbs, Raymond R. ; Cook, J. R. ; Weisenburger, Dennis D. ; Chan, Wing C. ; Pierce, Susan K. ; Staudt, Louis M. / Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. In: Nature. 2010 ; Vol. 463, No. 7277. pp. 88-92.
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abstract = "A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD11 is required for constitutive NF-B pathway activity and survival in ABC DLBCL. Roughly 10{\%} of ABC DLBCLs have mutant CARD11 isoforms that activate NF-B, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig-, CD79A and CD79B) killed ABC DLBCLs with wild-type CARD11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18{\%} of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.",
author = "Davis, {R. Eric} and Ngo, {Vu N.} and Georg Lenz and Pavel Tolar and Young, {Ryan M.} and Romesser, {Paul B.} and Holger Kohlhammer and Laurence Lamy and Hong Zhao and Yandan Yang and Weihong Xu and Shaffer, {Arthur L.} and George Wright and Wenming Xiao and John Powell and Jiang, {Jian Kang} and Thomas, {Craig J.} and Andreas Rosenwald and German Ott and Muller-Hermelink, {Hans Konrad} and Gascoyne, {Randy D.} and Connors, {Joseph M.} and Johnson, {Nathalie A.} and Rimsza, {Lisa M} and Elias Campo and Jaffe, {Elaine S.} and Wilson, {Wyndham H.} and Jan Delabie and Smeland, {Erlend B.} and Fisher, {Richard I.} and Braziel, {Rita M.} and Tubbs, {Raymond R.} and Cook, {J. R.} and Weisenburger, {Dennis D.} and Chan, {Wing C.} and Pierce, {Susan K.} and Staudt, {Louis M.}",
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AU - Davis, R. Eric

AU - Ngo, Vu N.

AU - Lenz, Georg

AU - Tolar, Pavel

AU - Young, Ryan M.

AU - Romesser, Paul B.

AU - Kohlhammer, Holger

AU - Lamy, Laurence

AU - Zhao, Hong

AU - Yang, Yandan

AU - Xu, Weihong

AU - Shaffer, Arthur L.

AU - Wright, George

AU - Xiao, Wenming

AU - Powell, John

AU - Jiang, Jian Kang

AU - Thomas, Craig J.

AU - Rosenwald, Andreas

AU - Ott, German

AU - Muller-Hermelink, Hans Konrad

AU - Gascoyne, Randy D.

AU - Connors, Joseph M.

AU - Johnson, Nathalie A.

AU - Rimsza, Lisa M

AU - Campo, Elias

AU - Jaffe, Elaine S.

AU - Wilson, Wyndham H.

AU - Delabie, Jan

AU - Smeland, Erlend B.

AU - Fisher, Richard I.

AU - Braziel, Rita M.

AU - Tubbs, Raymond R.

AU - Cook, J. R.

AU - Weisenburger, Dennis D.

AU - Chan, Wing C.

AU - Pierce, Susan K.

AU - Staudt, Louis M.

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