NEOPLASIA A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival

Multiple myeloma (MM) is a B-cell neo-plasm that is characterized by the clonal expansion of malignant plasma cells and is frequently associated with chromo-somal translocations placing an onco-gene under the control of the immuno-globulin heavy chain enhancer. Despite these pathogenic translocations, MM cells remain dependent on external cues for survival. We present evidence that brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors, and its high-affinity recep-tor, tropomyosin receptor kinase B (TrkB), contribute to these survival cues. MM cells express TrkB, and respond to BDNF by activating mitogen-activated protein kinase (MAPK) and phosphatidylinosi-tol-3 kinase–a PI3K target (PI3K/Akt) sig-naling cascades. Addition of BDNF pro-tects human MM cell lines (HMCLs) from apoptosis induced by dexamethasone or bortezomib and prolongs the survival of primary MM cells cultured alone or with human bone marrow (BM) stroma. As BDNF and TrkB are expressed by osteo-blasts, stromal cells, and endothelial cells within the BM microenvironment, a BDNF-TrkB axis may be critical to the interac-tions of MM with bone and stroma that contribute to MM tumor progression. Fi-nally, BDNF is expressed by malignant plasma cells isolated from a subset of patients with MM, as well as by most HMCLs, suggesting a potential role for this neurotrophin axis in autocrine as well as paracrine support of MM. (Blood