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

Abstract

Multiple myeloma (MM) is a B-cell neo IntroductionMultiple myeloma (MM) is a B-cell neoplasm, characterized by the clonal expansion of malignant plasma cells, and frequently associated with chromosomal translocations placing an oncogene under the control of the immunoglobulin heavy chain enhancer. 1 These translocations typically occur during immunoglobulin heavy chain switch recombination, but they may also occur as a result of errors in somatic hypermutation. Recurrent translocation partners deregulated in MM include cyclin D1 and cyclin D3, the transcription factors c-musculoaponeurotic fibrosarcoma (c-MAF) and myeloma SET (single exon transfer) domain (MMSET), and fibroblast growth factor receptor 3 (FGFR3). Despite these pathogenic translocations, malignant plasma cells retain their dependency on external signals for survival. Such signals include interleukin 6 (IL-6), insulin-like growth factor-1 (IGF-1), hemopoietic growth factor, basic fibroblast growth factor, B-lymphocyte stimulator (BLyS), and integrin-mediated cellular contact. [2][3][4][5][6][7] We present evidence that neurotrophin-receptor interactions, involving brainderived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), contribute to the survival signals necessary for MM tumor progression.The neurotrophin family of growth factors includes BDNF, NGF (nerve growth factor), and NT-4/5 (neurotophin-4/5). Each neurotrophin binds to a specific Trk: NGF binds to TrkA, BDNF and NT-4/5 bind to TrkB, and NT-3 binds to TrkC. In addition, neurotrophins share a common receptor, p75 NTR , a member of the tumor necrosis factor (TNF) receptor superfamily. 8 Although structurally related to TNF, neurotrophins are secreted as homodimers rather than trimers and induce receptor dimerization rather than trimerization. Trk receptor dimerization triggers kinase activation and the initiation of signaling cascades, including MEK/MAPK (mitogen-activated protein kinase kinasemitogen-activated protein kinase) and PI3K/Akt (phosphatidylinositol-3 kinase-a PI3K target), that favor cellular survival. 9 In contrast, p75 NTR engagement triggers divergent pathways to modulate survival, cell cycle regulation, and cytoskeletal rearrangement. 9 Thus, while p75 NTR binding can increase the affinity and specificity of Trk-neurotrophin interactions, p75 NTR can also induce apoptosis when Trk activation is reduced or absent. 10,11 The overall cellular response to neurotrophin exposure reflects a balance between p75 NTR and Trk engagement.Neurotrophins are synthesized as proneurotrophins and are enzymatically cleaved to yield mature proteins. Cleavage can occur either intracellularly, by the action of furin or proconvertase, or extracellularly, by the action of plasmin, matrix metalloproteinase 7 (MMP-7) or 12 Both mature neurotrophins and proneurotrophins are biologically active, with divergent roles that reflect differing receptor affinities: proneurotrophins display greater affinities for p75 NTR , whereas mature neurotrophins displa...

Neurotrophins and B-cell malignancies

“…This group also found low-intermediate levels of Trk expression, though Trk type was not determined [127]. This confirmed earlier reports where full length TrkB mRNA and protein were seen in RPMI-8226 [129]. Constitutive TrkB expression was seen in KMS11, RPMI-8226 and LP1 cells, with low TrkB levels increasing on dexamethasone exposure in OPM1, U266, JJN3, H929 and UTMC2 cell lines.…”

“…In contrast, p75 NTR was not detected in any of the MM cell lines used. Following on from the increased TrkB expression after dexamethasone exposure, cell survival was examined and BDNF was shown to protect RPMI-8226 cells from dexamethasone-induced apoptosis [129]. As expected, in the absence of its receptors, NGF had no effect on survival.…”

“…They found that MM patients produced pro and mature BNDF mRNA, and increased BDNF in one marrow sample from MM patients in comparison to control (though the cellular source of BDNF was undetermined; [129]. Full length TrkB was found in 24/25 patients samples tested, with no p75 NTR detected at either mRNA or protein levels.…”

“…In contrast to DLBCL cells, several mutiple myeloma (MM) cell lines (including RPMI-8226), were found to produce functional BDNF (as shown by PC12 neurite outgrowth; [129]). However BDNF expression and secretion from these cells is controversial, as a more recent report did not fine BDNF expression in the RPMI-8226 MM cell line.…”

“…BDNF could also delay bortezomib-induced apoptosis in JJN3 cells, but not prevent it. This is thought to be partly due to activation of PI3K signaling [129].…”