Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL

Abstract

IntroductionClassical Hodgkin lymphoma (HL) is a lymphoid neoplasm that stems from the clonal expansion of mononuclear Hodgkin cells and multinuclear Reed-Sternberg cells expressing the CD30 antigen. 1 Malignant Hodgkin and Reed-Sternberg (HRS) cells usually constitute less than 10% of the neoplastic mass. 2 The remaining tissue is composed of a reactive cellular infiltrate. Although rare cases with T-cell genotype have been described, 3,4 the vast majority of classical HL tumors is thought to originate from transformed germinal center (GC) B cells, because their HRS component harbors a monoclonal immunoglobulin (Ig) gene rearrangement and somatically mutated Ig V region genes. 1,[5][6][7] Despite their GC B-cell origin, HRS cells lack many molecules usually expressed by B cells and are incapable of producing functional Igs. [7][8][9][10][11][12] While nonmalignant B cells that have lost their capacity to express Igs rapidly undergo apoptosis, 13 malignant HRS cells survive. This abnormal survival is thought to be due to dysregulated activation of nuclear factor B (NF-B), 14-18 a transcription factor essential for the development of both normal and neoplastic B cells. 19,20 In classical HL, the reactive infiltrate is composed of nonmalignant T cells, B cells, plasma cells, and myeloid cells, including macrophages and granulocytes. 2,21 These cells are thought to enhance HRS cell growth through cytokines and tumor necrosis factor (TNF) family members, such as CD30 ligand (CD30L), receptor activator of NF-B ligand (RANKL), and CD40 ligand (CD40L). 15,[22][23][24][25][26][27][28][29] Recent studies show that myeloid cells express B-cell-activating factor of the TNF family (BAFF, also known as BLyS) and its homolog APRIL, a proliferation-inducing ligand, [30][31][32][33] 2 molecules essential for the survival, proliferation, and differentiation of B cells and plasma cells. 34,35 BAFF activates B cells and plasma cells by binding to transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B-cell maturation antigen (BCMA), and BAFF receptor (BAFF-R) receptors. APRIL activates B cells and plasma cells by binding to TACI and BCMA, but not BAFF-R. 36 By recruiting TNF receptor-associated factor (TRAF) adaptor molecules, TACI, BCMA, and BAFF-R activate an IB kinase (IKK) complex that in turn elicits phosphorylation-dependent degradation of inhibitor of NF-B (IB), which retains p50, c-Rel, and p65 NF-B proteins in a cytoplasmic inactive form. [37][38][39] IB degradation causes NF-B nuclear translocation and transcriptional activation of NF-B-responsive genes involved in B-cell survival, proliferation, and maturation. 31,[39][40][41] Of note, recent studies show that APRIL signaling via TACI and BCMA receptors is reinforced by heparan sulfate proteoglycans (HSPGs) anchored on the cell membrane or associated with the extracellular matrix. 35,42,43 The role of TACI, BCMA, BAFF-R, and HSPGs in HL remains unknown.BAFF and APRIL are implicated in B-cell neoplasias, 44-52 including non-Hodgkin lymph...

Blocking the APRIL circuit enhances acute myeloid leukemia cell chemosensitivity

“…The anti-apoptotic protein Bcl-2 is induced by APRIL in B-cell lymphoma. 2,3 Since high Bcl-2 expression is associated with poor chemotherapy response, 11,12 we investigated the relationship between APRIL and Bcl-2 in AML. Western blotting analysis showed that exogenous expression of APRIL up-regulated Bcl-2 in CD34 + cells, whereas APRIL neutralization resulted in Bcl-2 downregulation in primary AML cells ( Figure 3A, B), suggesting that APRIL protects AML from chemothereutic drugs through the upregulation of Bcl-2.…”

“…APRIL (a proliferation-inducing ligand), is a member of the TNF superfamily expressed in B-cell progenitors, monocytes, dendritic cells, and megakaryoblasts, which may contribute to the development of B-cell malignancies, including non-Hodgkin's lymphoma (NHL), B-CLL and multiple myeloma (MM), through the enhancement of cell survival and proliferation. [1][2][3][4][5][6] APRIL is a homotrimeric type 2 transmembrane protein that also exists in soluble form deriving from the intracellular cleavage of the full-length protein. It can bind with high affinity to two members of the TNFreceptor superfamily, the B-cell maturation antigen (BCMA) and the transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI).…”

Crosstalk via the NF-κB signaling system

“…Furthermore, a significant fraction of the malignant Reed Sternberg cells in Hodgkin lymphoma have been shown to harbor functionally defective iκbα gene (Krappmann et al, 1999). But more recently is was shown that signaling by BAFF is critical not only for promoting survival of these diseased cells, but also their growth and proliferation (Chiu et al, 2007). Finally, it is remarkable that components of the non-canonical pathway, such as LTβR, NIK, or NFκB2, are more often found to be mutated or misregulated in multiple myeloma than components of the canonical NF-κB pathway.…”

Knockdown of a Proliferation-inducing Ligand (PRIL) Suppresses the Proliferation of Gastric Cancer Cells

“…APRIL is expressed by a subset of immune cells that also produce B-cell activating factor (BAFF): monocytes, macrophages, (Hahne et al, 1998;Nardelli et al, 2001;He et al, 2004;Chu et al, 2007) as well as in some non-immune cells such as epithelial cells and osteoclasts. Moreover, PRIL is abundantly expressed in a variety of tumor cells and tissues, such as lung carcinomas, melanoma (Roth et al, 2001;Stein et al, 2002), lymphoid malignancies (Nardelli et al, 2001;Deshayes et al, 2004;Kern et al, 2004;Moreaux et al, 2004;Chiu et al, 2007;Pelekanou et al, 2008;Yaccoby et al, 2008) and in particular gastrointestinal tumors including rectum, duodenum, colon, stomach and esophagus (Hahne et al, 1998;Kelly et al, 2000).…”