Abstract
BackgroundMultiple myeloma (MM) is a malignancy of terminally-differentiated plasma cells, and the second most prevalent blood cancer. At present there is no cure for MM, and the average prognosis is only three to five years. Current treatments such as chemotherapy are able to prolong a patient's life but rarely prevent relapse of the disease. Even hematopoietic stem cell transplants and novel drug combinations are often not curative, underscoring the need for a continued search for novel therapeutics. CD137 and its ligand are members of the Tumor Necrosis Factor (TNF) receptor and TNF superfamilies, respectively. Since CD137 ligand cross-linking enhances proliferation and survival of healthy B cells we hypothesized that it would also act as a growth stimulus for B cell cancers.Methodology/Principal FindingsProliferation and survival of B cell lymphoma cell lines were not affected or slightly enhanced by CD137 ligand agonists in vitro. But surprisingly, they had the opposite effects on MM cells, where CD137 ligand signals inhibited proliferation and induced cell death by apoptosis. Furthermore, secretion of the pro-inflammatory cytokines, IL-6 and IL-8 were also enhanced in MM but not in non-MM cell lines in response to CD137 ligand agonists. The secretion of these cytokines in response to CD137 ligand signaling was consistent with the observed activation of the classical NF-κB pathway. We hypothesize that the induction of this pathway results in activation-induced cell death, and that this is the underlying mechanism of CD137-induced MM cell death and growth arrest.Conclusions/SignificanceThese data point to a hitherto unrecognized role of CD137 and CD137 ligand in MM cell biology. The selective inhibition of proliferation and induction of cell death in MM cells by CD137 ligand agonists may also warrant a closer evaluation of their therapeutic potential.
Highlights
Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells that primarily resides at multiple sites in the bone marrow and is clinically characterized by osteolytic lesions, immunodeficiency, and renal disease
The constitutive expression of CD137 ligand by primary B cells provides the molecular basis for B cells to receive costimulatory signals from CD137 [26,27]
CD137 inhibits proliferation of MM cells Since CD137 ligand crosslinking enhances proliferation of preactivated B cells, we tested this activity in B cell lines [22,28]
Summary
Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells that primarily resides at multiple sites in the bone marrow and is clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. Agents with novel mechanisms of action, such as the proteasome inhibitor, bortezomib and immunomodulatory drugs like thalidomide and lenalidomide have shown promise for treatment of patients with refractory and relapsed disease, and for those with previously untreated multiple myeloma [4,5]. Even with these novel drugs, the majority of MM patients eventually experience relapse, their disease becomes chemoresistant, and they die of the disease [6,7]. Since CD137 ligand cross-linking enhances proliferation and survival of healthy B cells we hypothesized that it would act as a growth stimulus for B cell cancers
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