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 Blood, 21 May 2009, Vol. 113, No. 21, pp. 5206-5216.
Prepublished online as a Blood First Edition Paper on March 25, 2009; DOI 10.1182/blood-2008-09-179762.

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LYMPHOID NEOPLASIA

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 Gupta1, Stacey R. Dillon2, Steven C. Ziesmer1, Andrew L. Feldman3, Thomas E. Witzig1, Stephen M. Ansell1, James R. Cerhan4, and Anne J. Novak1

1 Division of Hematology, Mayo Clinic, Rochester, MN; 2 ZymoGenetics, Seattle, WA; and 3 Department of Lab Medicine and Pathology, and 4 Division of Epidemiology, Mayo Clinic, Rochester, MN

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.


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