A proliferation-inducing ligand mediates follicular lymphoma B-cell proliferation and cyclin D1 expression through phosphatidylinositol 3-kinase-regulated mammalian target of rapamycin activation

Mamta Gupta, Stacey R. Dillon, Steven C. Ziesmer, Andrew L. Feldman, Thomas E. Witzig, Stephen M. Ansell, James R. Cerhan, Anne J. Novak

Research output: Contribution to journalArticle

41 Scopus citations

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 upregulation 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.

Original languageEnglish (US)
Pages (from-to)5206-5216
Number of pages11
JournalBlood
Volume113
Issue number21
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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