Kidins220/ARMS is an essential modulator of cardiovascular and nervous system development

The growth factor family of neurotrophins has major roles both inside and outside the nervous system. Here, we report a detailed histological analysis of key phenotypes generated by the ablation of the Kinase D interacting substrate of 220 kDa/Ankyrin repeat-rich membrane spanning (Kidins220/ARMS) protein, a membrane-anchored scaffold for the neurotrophin receptors Trk and p75NTR. Kidins220 is important for heart development, as shown by the severe defects in the outflow tract and ventricle wall formation displayed by the Kidins220 mutant mice. Kidins220 is also important for peripheral nervous system development, as the loss of Kidins220 in vivo caused extensive apoptosis of DRGs and other sensory ganglia. Moreover, the neuronal-specific deletion of this protein leads to early postnatal death, showing that Kidins220 also has a critical function in the postnatal brain

Anti-apoptotic role and clinical relevance of neurotrophins in diffuse large B-cell lymphomas

International audienceBackground: Diffuse large B-cell lymphoma (DLBCL) is a fatal malignancy that needs to identify new targets for additional therapeutic options. This study aimed to clarify the clinical and biological significance of endogenous neurotrophin (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) in DLBCL biopsy samples and cell lines.Methods: We analysed expression of NGF, BDNF, and their receptors (Trk, p75NTR) in 51 biopsies and cell lines by immunohistochemistry, immunofluorescence, and western blotting. To investigate the biological role of BDNF/TrkB/p75NTR axis, effects of neurotrophin signalling inhibition were determined on tumour cell survival and vascular endothelial growth factor (VEGF) secretion. The pharmacological pan-Trk inhibitor K252a was used for in vitro and in vivo studies.Results: A BDNF/TrkB axis was expressed in all biopsies, which was independent of the germinal centre B-cell (GCB)/non-GCB profile. p75NTR, TrkB, and BDNF tumour scores were significantly correlated and high NGF expression was significantly associated with MUM1/IRF4, and the non-GCB subtype. Diffuse large B-cell lymphoma cell lines co-expressed neurotrophins and their receptors. The full-length TrkB receptor was found in all cell lines, which was also phosphorylated at Tyr-817. p75NTR was associated to Trk and not to its cell death co-receptor sortilin. In vitro, inhibition of neurotrophin signalling induced cell apoptosis. K252a caused cell apoptosis, decreased VEGF secretion, and potentiated rituximab effect, notably in less rituximab-sensitive cells. In vivo, K252a significantly reduced tumour growth and potentiated the effects of rituximab in a GCB-DLBCL xenograft model.Conclusions: This work argues for a pro-survival role of endogenous neurotrophins in DLBCLs and inhibition of Trk signalling might be a potential treatment strategy for rituximab resistant subgroups

Neurotrophins and B-cell malignancies

Neurotrophins and their receptors act as important proliferative and pro-survival factors in a variety of cell types. Neurotrophins are produced by multiple cell types in both pro and mature forms, and can act in an autocrine or paracrine fashion. The p75NTR and Trk receptors can elicit signalling in response to the presence or absence of their corresponding neurotrophin ligands. This signalling, along with neurotrophin and receptor expression, varies between different cell types. Neurotrophins and their receptors have been shown to be expressed by and elicit signalling in B lymphocytes. In general, most neurotrophins are expressed by activated B cells and memory B cells. Likewise, the TrkB95 receptor is seen on activated B cells, while TrkA and p75NTR are expressed by both resting and active B cells as well as memory B cells. Nerve growth factor stimulates B cell proliferation, memory B cell survival, antibody production and CD40 expression. Brain derived neurotrophic factor is involved in B cell maturation in the bone marrow through TrkB95. Overall neurotrophins and their receptors have been shown to be involved in B cell proliferation, development, differentiation, antibody secretion and survival. As well as expression and activity in healthy B cells, the neurotrophins and their receptors can contribute to B cell malignancies including acute lymphoblastic leukaemia, diffuse large B cell lymphoma, Burkitt’s lymphoma and multiple myeloma. They are involved in B cell malignancy survival and potentially in drug resistance.Molecular Medicine Ireland as part of the Clinical & Translational Research Scholars Programme2016-09-2