title: A proliferation-inducing ligand mediates follicular lymphoma B-cell proliferation and cyclin D1 expression through phosphatidylinositol 3-kinase-regulated mammalian target of rapamycin activation.
abstract: A proliferation-inducing ligand (APRIL), as well as its receptors transmembrane activator and calcium-modulating cyclophilin ligand (CAML) interactor (TACI) and B-cell maturation antigen (BCMA), has been shown to be important in B-cell biology, and overexpression of APRIL in mice results in development of lymphoma. Limited data are available on APRIL-specific signaling responses, but knockout models suggest that signaling through TACI is critical to B-cell homeostasis. To better understand the mechanism by which APRIL exerts its effects and how it may contribute to lymphomagenesis, we sought to characterize the outcome of APRIL-TACI interactions. In support of murine studies, we find that APRIL induces proliferation of human patient follicular lymphoma (FL) B cells in a TACI-dependent manner. This study also shows that APRIL is expressed within the tumor microenvironment and that, upon engagement with TACI, APRIL mediates activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Activation of PI3K via APRIL results in phosphorylation of Akt and mammalian target of rapamycin (mTOR) and the mTOR-specific substrates p70S6 kinase and 4E-binding protein 1 in a TACI-dependent manner. APRIL-mediated signaling also results in phosphorylation of Rb and up-regulation of cyclin D1. These studies are the first to characterize APRIL-TACI-specific signaling and suggest a role for this ligand-receptor pair in FL B-cell growth.
authors.affiliation: Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Mamta
authors.initials: M
authors.lastname: Gupta
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Dillon
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ziesmer
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldman
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak