Lymphoma B Cells Evade Apoptosis through the TNF Family Members BAFF/BLyS and APRIL

Abstract

The mechanisms underlying the autonomous accumulation of malignant B cells remain elusive. We show in this study that non-Hodgkin’s lymphoma (NHL) B cells express B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), two powerful B cell-activating molecules usually expressed by myeloid cells. In addition, NHL B cells express BAFF receptor, which binds BAFF, as well as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation Ag (BCMA), which bind both BAFF and APRIL. Neutralization of endogenous BAFF and APRIL by soluble TACI and BCMA decoy receptors attenuates the survival of NHL B cells, decreases activation of the prosurvival transcription factor NF-κB, down-regulates the antiapoptotic proteins Bcl-2 and Bcl-xL, and up-regulates the proapoptotic protein Bax. Conversely, exposure of NHL B cells to recombinant or myeloid cell-derived BAFF and APRIL attenuates apoptosis, increases NF-κB activation, up-regulates Bcl-2 and Bcl-xL, and down-regulates Bax. In some NHLs, exogenous BAFF and APRIL up-regulate c-Myc, an inducer of cell proliferation; down-regulate p53, an inhibitor of cell proliferation; and increase Bcl-6, an inhibitor of B cell differentiation. By showing that nonmalignant B cells up-regulate BAFF and APRIL upon stimulation by T cell CD40 ligand, our findings indicate that NHL B cells deregulate an otherwise physiological autocrine survival pathway to evade apoptosis. Thus, neutralization of BAFF and APRIL by soluble TACI and BCMA decoy receptors could be useful to dampen the accumulation of malignant B cells in NHL patients.

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).…”

Apoptosis in the development of the immune system

“…96,97 Indeed, constitutive activation of the NF-kB pathway results in B-cell hyperplasia and obviated the BAFF-R-dependence of B-cell development. It also blocked the nuclear translocation of protein kinase C-d, which had been shown to induce the death of B-cells by phosphorylating histone H2B upon growth factor withdrawal.…”

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

“…In contrast to most TNF family members, APRIL is processed in the Golgi apparatus into the active soluble form by a furin convertase (Lopez-Fraga et al, 2001). 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).…”