Caractérisation fonctionnelle du récepteur de type 2 de la neurotensine dans la résistance à la mort cellulaire des lymphocytes B au cours de la Leucémie Lymphoïde Chronique

Abstract : Chronic lymphocytic leukemia (CLL) is characterized by the abnormal accumulation of mature B lymphocytes. Current therapies for CLL rely on using kinase inhibitors targeting B-cell receptor (BCR) pathways, but they are limited by the high level of apoptosis-resistant B-CLL cells, which results in a high frequency of patient relapse. Because current therapies fail to eradicate these apoptosis-resistant cells, it is essential to identify alternative survival pathways as novel targets for anticancer therapies. Overexpression of cell-surface G protein-coupled receptors (GPCRs) drives cell transformation, and thus plays a critical role in malignancies. In this study, we show that neurotensin receptor 2 (NTSR2), a G-protein-coupled receptor, is an essential driver of apoptosis resistance in B-CLL. NTSR2 was highly expressed and constitutively active in B-CLL cells, and its activation depended on its interaction with the tropomyosin-related kinase B receptor (TrkB) and the recruitment of Gi proteins, instead of its interaction with its natural ligand, neurotensin (NTS). The NTSR2-TrkB interaction acted as a conditional oncogenic driver requiring the TrkB ligand BDNF (Brain-Derived Neurotrophic Factor), which is highly expressed in B-CLL cells, unlike its natural ligand NTS. The NTSR2-TrkB interaction activates survival signaling pathways, including the Src and AKT kinase pathways, as well as expression of the anti-apoptotic proteins Bcl-2 (B-cell lymphoma-2) and Bcl-xL (B-cell lymphoma-extra large). TrkB failed to protect B-CLL cells from a drastic decrease in viability via typical apoptotic cell death when NTSR2 was down-regulated. Taken together, the results suggest that the NTSR2-TrKB interaction and the sustained activation of signaling pathways reliant on this interaction constitute an essential driving force for apoptosis evasion of B-CLL cells. Targeting NTSR2 could represent a promising strategy for treating B-CLL malignancy.
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Amazigh Abbaci. Caractérisation fonctionnelle du récepteur de type 2 de la neurotensine dans la résistance à la mort cellulaire des lymphocytes B au cours de la Leucémie Lymphoïde Chronique. Médecine humaine et pathologie. Université de Limoges, 2017. Français. ⟨NNT : 2017LIMO0029⟩. ⟨tel-01881459⟩

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