Submitted September 17, 2008
Accepted March 8, 2009
APRIL mediates follicular lymphoma B cell proliferation and cyclin D1 expression through PI3-kinase regulated mTOR activation
Mamta Gupta, Stacey R. Dillon, Steven C. Ziesmer, Andrew L. Feldman, Thomas E. Witzig, Stephen M. Ansell, James R. Cerhan, and Anne J. Novak*
Division of Hematology, Mayo Clinic, Rochester, MN, United States
ZymoGenetics, Seattle, WA, United States
Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
Division of Epidemiology, Mayo Clinic, Rochester, MN, United States
* Corresponding author; email: novak.anne{at}mayo.edu.
APRIL, as well as its receptors TACI and BCMA, has been also shown to be important in B cell biology and over-expression of APRIL in mice results in development of lymphoma. Limited data are available on APRIL-specific signaling 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 PI3-kinase pathway. Activation of PI3K via APRIL results in phosphorylation of Akt and mTOR and the mTOR specific substrates p70S6 kinase and 4E-BP1 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.
