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 development and function and dysregulates genes required for sympathoadrenal lineage differentiation. We discovered that KIF1Bβ mediates anterograde transport of the NGF receptor TRKA and is required for NGF-dependent neuronal differentiation. Moreover, TRKA transport is impeded by pathogenic KIF1Bβ mutations identified in neuroblastoma. We observed reduced expression of neuronal differentiation proteins in KIF1Bβ deficient mouse neuroblasts and primary human neuroblastomas that lack KIF1Bβ. Furthermore, transcriptomic analyses revealed that loss of KIF1Bβ in mouse sympathetic neuroblasts causes changes in gene expression similar to those seen in high-risk neuroblastoma, independent of MYCN amplification and the loss of genes neighbouring KIF1B on chromosome 1p36.

Thus, defective precursor cell differentiation, and impaired apoptosis, common traits of aggressive childhood malignancies, are pathogenic effects of KIF1Bβ loss in neuroblastoma.

List of scientific papers

I. Chen ZX, Wallis K, Fell SM, Sobrado VR, Hemmer MC, Ramskold D, Hellman U, Sandberg R, Kenchappa RS, Martinson T, Johnsen JI, Kogner, P, Schlisio S. RNA Helicase A Is a Downstream Mediator of KIF1B Tumor-Suppressor Function in Neuroblastoma. Cancer Discovery. (2014) 4, 434–451.
https://doi.org/10.1158/2159-8290.CD-13-0362

II. Li S, Fell SM, Surova O, Smedler E, Wallis K, Chen ZX, Hellman U, Johnsen JI, Martinsson T, Kenchappa RS, Uhlén P, Kogner P, Schlisio S. The 1p36 Tumor Suppressor KIF1Bβ Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis. Developmental Cell. (2016) 36, 164–178.
https://doi.org/10.1016/j.devcel.2015.12.029

III. Fell SM, Li S, Wallis K, Kock A, Surova O, Rraklli V, Höfig C, Mittag J, Arsenian Henriksson M, Kenchappa RS, Holmberg J, Kogner P, Schlisio S. KIF1Bβ links neuroblastoma and neurodegenerative disease through anterograde transport of TRKA. [Manuscript]