Lymphoma B Cells Evade Apoptosis through the TNF Family Members BAFF/B-LyS and APRIL

Bing He, Amy Chadburn, Erin Jou, Elaine J. Schattner, Daniel M. Knowles, Andrea Cerutti

Research output: Contribution to journalArticlepeer-review

253 Scopus citations

Abstract

The mechanisms underlying the autonomous accumulation of malignant B cells remain elusive. We show in this study that non-Hodgkin's lymphoma (NHL) B cells express B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), two powerful B cell-activating molecules usually expressed by myeloid cells. In addition, NHL B cells express BAFF receptor, which binds BAFF, as well as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation Ag (BCMA), which bind both BAFF and APRIL. Neutralization of endogenous BAFF and APRIL by soluble TACI and BCMA decoy receptors attenuates the survival of NHL B cells, decreases activation of the prosurvival transcription factor NF-κB, down-regulates the antiapoptotic proteins Bcl-2 and Bcl-XL, and up-regulates the proapoptotic protein Bax. Conversely, exposure of NHL B cells to recombinant or myeloid cell-derived BAFF and APRIL attenuates apoptosis, increases NF-κB activation, up-regulates Bcl-2 and Bcl-xL, and down-regulates Bax. In some NHLs, exogenous BAFF and APRIL up-regulate c-Myc, an inducer of cell proliferation; down-regulate p53, an inhibitor of cell proliferation; and increase Bcl-6, an inhibitor of B cell differentiation. By showing that nonmalignant B cells up-regulate BAFF and APRIL upon stimulation by T cell CD40 ligand, our findings indicate that NHL B cells deregulate an otherwise physiological autocrine survival pathway to evade apoptosis. Thus, neutralization of BAFF and APRIL by soluble TACI and BCMA decoy receptors could be useful to dampen the accumulation of malignant B cells in NHL patients.

Original languageEnglish
Pages (from-to)3268-3279
Number of pages12
JournalJournal of Immunology
Volume172
Issue number5
DOIs
StatePublished - 1 Mar 2004
Externally publishedYes

Fingerprint

Dive into the research topics of 'Lymphoma B Cells Evade Apoptosis through the TNF Family Members BAFF/B-LyS and APRIL'. Together they form a unique fingerprint.

Cite this