B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy?

Abstract

Multiple myeloma (MM) is a currently incurable malignancy of plasma cells. Malignant myeloma cells (MMCs) are heavily dependent upon the bone marrow (BM) microenvironment for their survival. One component of this tumor microenvironment, B-Cell Activating Factor (BAFF), has been implicated as a key player in this interaction. This review discusses the role of BAFF in the pathophysiology of MM, and the potential of BAFF-inhibitory therapy for the treatment of MM. Multiple studies have shown that BAFF functions as a survival factor for MMCs. Furthermore, MMCs express several BAFF-binding receptors. Of these, only Transmembrane Activator and CAML Interactor (TACI) correlates with the MMC's capability to ligate BAFF. Additionally, the level of expression of TACI correlates with the level of the MMC's BM dependency. Ligation of BAFF receptors on MMCs causes activation of the Nuclear Factor of κ-B (NF-κB) pathway, a crucial pathway for the pathogenesis of many B-cell malignancies. Serum BAFF levels are significantly elevated in MM patients when compared to healthy controls, and correlate inversely with overall survival. BAFF signaling is thus an interesting target for the treatment of MM. Several BAFF-inhibitory drugs are currently under evaluation for the treatment of MM. These include BAFF-monoclonal antibodies (tabalumab) and antibody-drug conjugates (GSK2857916).

The role of BAFF in the progression of rheumatoid arthritis

“…Thus, BAFF/4BAFF heterotrimers can function as dominant negative antagonists to the activity of BAFF [9]. The production of BAFF is accomplished predominantly by monocytes, dendritic cells (DCs), macrophages, astrocytes, fibroblast-like synoviocytes (FLS) and neutrophils [10,11].…”

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

“…These bidirectional interactions support the survival, proliferation, and homing of MM cells and contribute to drug resistance. Moreover, these interactions result in osteolysis, increased angiogenesis, and immune suppression [15–17]. …”

Binding of B‐cell maturation antigen to B‐cell activating factor induces survival of multiple myeloma cells by activating Akt and JNK signaling pathways

“…Soluble BCMA has been reported to be highly expressed in the serum of myeloma patients and correlated with disease progression and poor prognosis. In addition to MM, BCMA has also been reported to induce the proliferation and survival of Hodgkin's disease cell line . These findings suggest that the BAFF/APRIL–BCMA axis is probably essential in plasma cell physiology.…”

“…B cell‐activating factor can activate canonical or non‐canonical NF‐κB pathways, mitogen‐activated protein‐kinase pathways such as JNK and the phosphatidylinositol 3‐kinase pathway. The activation of these signalling pathways prolonged the survival of MM cells and increased their proliferation . Binding of BAFF to BCMA, TACI or BAFF‐R could activate either the canonical or non‐canonical NF‐κB pathways, which in turn, up‐regulated the anti‐apoptotic proteins and down‐regulated the pro‐apoptotic proteins by excluding protein kinase‐Cδ (PKCδ) from the nucleus .…”