Résistance des lymphocytes B à la mort cellulaire au cours de la leucémie lymphoïde chronique : implications d'une neurotrophine, le BDNF, du récepteur de la neurotensine, NTSR2, et des "nurse-like cells"

Abstract : Chronic lymphocytic leukemia (CLL) is a malignant hemopathy characterized by the accumulation of apoptosis resistant mature B lymphocytes in peripheral blood and secondary lymphoid organs. In these secondary lymphoid organs, the tumor microenvironment, notably Nurse-like Cells (NLCs), plays a major role in leukemic cells survival and proliferation promotion. In this study, an overexpression of neurotensin receptor NTSR2, a G-protein coupled receptor, was identified. NTSR2 is constitutively activated in circulating leukemic cells and its activation depends on its interaction with tyrosine kinase activity receptor TrkB upon binding of its ligand, BDNF. Activation of NTSR2-TrkB by BDNF induces survival signaling by Src and Akt pathways, and in term anti-apoptotic proteins Bcl-2 and Bcl-XL overexpression. Inhibition of NTSR2 in those cells impacts their viability. In the presence of NLCs, expressions of NTSR2, TrkB, BDNF, and sortilin, a neurotrophin and Trk receptor transport regulator, are enhanced. NLCs produce BDNF, stimulate Src activation, and their protective role on leukemic cells is BDNF-dependent. Taken together, this study highlights a key role of NTSR2-TrkB-BDNF in leukemic cells survival signaling, both in the circulation or in the tumor microenvironment, and might thus constitute a potential new therapeutic target.
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Hugo Talbot. Résistance des lymphocytes B à la mort cellulaire au cours de la leucémie lymphoïde chronique : implications d'une neurotrophine, le BDNF, du récepteur de la neurotensine, NTSR2, et des "nurse-like cells". Médecine humaine et pathologie. Université de Limoges, 2018. Français. ⟨NNT : 2018LIMO0066⟩. ⟨tel-02440681⟩

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