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 phosphatidyl- IntroductionThere is accumulating evidence that implicates the tumor necrosis factor (TNF) superfamily members B-cell-activating factor (BAFF; TNFSF13B), also called B lymphocyte stimulator, 1,2 and a proliferation-inducing ligand (APRIL; TNFSF13), 3 as well as their receptors, as critical factors for the growth and survival of both normal and malignant B cells. 4 In vivo studies of APRIL have shown that administration of recombinant soluble APRIL to mice results in increased spleen weight and an increased proportion of B cells in the spleen, 5 and transgenic overexpression of APRIL in mice results in B-cell hyperplasia and lymphoma, suggesting a significant role for this protein in malignant B-cell biology. 6 Whereas the studies performed to date highlight a role for APRIL in murine models, the significance of this protein on human B-cell biology, normal or malignant, is poorly understood, although initial work suggests that, similar to BAFF, APRIL supports lymphoma B-cell survival. 7,8 The downstream signaling cascades activated upon APRIL binding that may be involved in tumor formation are also yet to be characterized.Two receptors, B-cell maturation antigen (BCMA; TNFRSF17) 9 and transmembrane activator and calcium-modulating cyclophilin ligand (CAML) interactor (TACI; TNFRSF13B), 10 have been identified as receptors for BAFF and APRIL. APRIL does not bind to BAFF-receptor (BAFF-R; TNFRSF13C), which is the primary receptor for BAFF on mature B cells. 11,12 The significance of BCMA in B-cell function remains to be fully elucidated, but there is growing evidence that this receptor is important in normal and malignant plasma cell biology. 13 An important role for TACI in B-cell homeostasis has been implicated from TACI-deficient mice that were found to have an accumulation of B cells, splenomegaly, and increased immunoglobulin production. [13][14][15][16] More recently, 2 groups have recently identified mutations in TACI as an important factor in common variable immunodeficiency and immunoglobulin A deficiency, both of which predispose to development of lymphom...

Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies

“…Similar staining was observed in all 10 specimens. These observations, in concert with similar results recently reported in diffuse large cell lymphoma, 26 follicular lymphoma, 33 T-cell ALL 34 and Philadelphia chromosome-positive ALL, 18 provide a potential rationale for targeting both complexes simultaneously.…”

FOXO1 is a tumor suppressor in classical Hodgkin lymphoma

“…14 At the same time, Hodgkin and Reed-Sternberg (HRS) cells express many genes of activated B cells, indicating that the oncogenic program of cHL may arise in the process of deregulation of mechanisms, controlling activity of NF-B, 15 ERK, 16 and JAK/STAT 17 pathways in activated B cells. In addition, AKT and ERK kinases are frequently constitutively activated in different B-lymphoma entities, including follicular lymphoma (FL), 18 diffuse large BCL (DLBCL), 19 Burkitt lymphoma (BL), 20 and cHL. 21,22 Therefore, it has been hypothesized that FOXO1 inactivation might be a common event contributing to lymphomagenesis in several lymphoma entities.…”

TLR4 ligation induces expression of APRIL molecule in human neutrophils — a preliminary study

“…Available data indicates tumor-promoting activity of APRIL, not only in various B-cell malignancies but also in human cancer of colon, thyroid or breast [26][27][28][29]. Moreaux et al demonstrated that APRIL activated NF-kB, PI-3kinase/AKT, and MAPK kinase pathways in myeloma cells and induced a strong up-regulation of the antiapoptotic proteins Mcl-1 and Bcl-2 [28].…”

“…Moreaux et al demonstrated that APRIL activated NF-kB, PI-3kinase/AKT, and MAPK kinase pathways in myeloma cells and induced a strong up-regulation of the antiapoptotic proteins Mcl-1 and Bcl-2 [28]. Gupta et al reported that APRIL mediates follicular lymphoma B-cell proliferation [29]. Furthermore, APRIL, through binding heparin sulfate proteoglycans (HSPG) on the surface of tumor cells, may ini- www.fhc.viamedica.pl tiate a solid tumor growth through the regulation of tumor cells adhesion and invasion [16,17].…”