The role of KIF1Bß in neuroblastoma tumour suppression during sympathetic neuron development

Neuroblastoma, the most common extra-cranial childhood tumour, is believed to arise from precursor cells of the sympathetic nervous system (neuroblasts). Hemizygous loss of chromosome 1p36 strongly correlates with poor prognosis in neuroblastoma and the 1p36 gene KIF1Bβ has been proposed to be a pathogenic target of this deletion. KIF1Bβ is required for normal developmental apoptosis of neuroblasts induced by competition for NGF during embryogenesis. We hypothesised that KIF1Bβ’s role in evelopmental culling of neuroblasts is a molecular mechanism that suppresses neuroblastoma development. In Paper I, we found that KIF1Bβ causes apoptosis through interaction with RNA helicase A (DHX9), promoting accumulation of DHX9 in the nucleus, and up-regulation of proapoptotic XIAP-associated factor 1 (XAF1). We demonstrate that NGF deprivation induced apoptosis requires DHX9 and that loss of KIF1Bβ expression in neuroblastomas with hemizygous deletion of 1p36 impairs DHX9 nuclear localization, implicating loss of DHX9 nuclear activity in neuroblastoma pathogenesis. In Paper II, we discovered that the Ca2+-dependent phosphatase calcineurin (CN) is activated by KIF1Bβ. CN mediates a diversity of cellular responses, and its activity is affected in various diseases. We show that KIF1Bβ effects mitochondrial dynamics through dephosphorylation of Dynamin-related protein 1 (DRP1) by CN, causing mitochondrial fission and apoptosis. We found that KIF1Bβ enables CN recognition of all known substrates, and DHX9, suggesting a general involvement of KIF1Bβ in CN signalling activity. DRP1 dephosphorylation or CN activity could not be stimulated by pathogenic KIF1Bβ mutations previously identified in neuroblastomas and ,0pheochromocytomas. Loss of KIF1Bβ and DRP1 expression in 1p36 hemizygous-deleted neuroblastomas, implies that dysregulation of mitochondrial dynamics and calcineurin activity affect high-risk and poor-prognosis neuroblastoma. In Paper III, we showed that loss of KIF1Bβ in the sympathetic nervous system impairs nervous ...