Death by rafting

Currently, monoclonal antibodies (mAbs) do not play a major role in the treatment of multiple myeloma (MM). In this issue of Blood, Yang and colleagues show that by disrupting structural cell integrity, mAbs against β2-microglobulin (β2M) have potent anti-MM activity.

Monoclonal antibodies have become a mainstay in the treatment of malignancies including lymphoproliferative disorders (anti-CD20, anti-CD52), breast cancer (anti–HER-2/neu), and colon cancer (anti-VEGF). These mAbs exert their antitumor effects through different mechanisms: direct induction of apoptosis; antibody-dependent, cell-mediated cytotoxicity; complement-mediated cytotoxicity; and inhibition of angiogenesis. In contrast, there is no mAb available for the treatment of MM.

It is well known that the bone marrow microenvironment is crucial for survival and proliferation of MM cells. Binding of MM cells to bone marrow stromal cells triggers the secretion of cytokines from the microenvironment, resulting in growth and survival of MM cells and resistance to conventional chemotherapy via signaling pathways such as JAK/STAT3, Ras/Raf/MAPK, and PI3K/Akt.^1,2  So far, approaches to disrupt the cytokine-mediated activation of signaling pathways have failed.³ 

Lipid rafts are cholesterol- and glycosphingolipid-enriched dynamic patches in the plasma membrane that act as platforms for conducting signals into cells. By reorganization of lipid rafts and exclusion of cytokine receptors from lipid rafts, growth-factor–mediated signaling could be completely blocked, and signaling pathways necessary for growth and survival of MM cells could be deactivated. In 2003, Podar et al reported that caveolae, specialized flask-shaped lipid rafts, are potential therapeutic targets in MM.⁴  Yang et al previously showed that anti-β₂M mAbs have remarkable tumoricidal activity in hematologic malignancies, both in vitro and in vivo.⁵  The current work of Yang and colleagues proposes that it may be possible to inhibit multiple cytokines critical for MM-cell growth and survival by targeting β₂M on the surface of MM cells. They now identify the mechanism of mAb-induced MM-cell death. They demonstrate that β₂M mAbs induce MM-cell apoptosis by recruiting major histocompatibility complex (MHC) class I molecules to lipid rafts, leading to subsequent activation of JNK and inhibition of PI3/Akt and MAPK pathways. Cytokines such as IL-6 and IGF-I, which play a critical role in the growth and survival of MM cells, were not able to rescue the cells from mAb-induced cell death. Yang and colleagues confirmed that binding of the mAb to β₂M resulted in structural reorganization of lipid rafts, excluded IL-6 and IGF-I receptors from the rafts, and blocked subsequent downstream signaling. Because the rafts are active platforms for conducting signals into cells, the modification of lipid-raft structure abrogated all cytokine-mediated JAK/STAT3, PI3K/Akt, and Ras/Raf/MAPK pathway signaling.

Several approaches to induce MM-cell death by neutralizing or blocking cytokines and subsequently disrupting the cytokine-mediated activation of signaling pathways have failed.³  In contrast, the disorganization of the structural integrity of the cell surface affects cellular functions by blocking cytokine-mediated signaling, and would be an ideal approach for the treatment of MM.