Abstract
Evading apoptosis and sustained survival signaling pathways are two central hallmarks of B-cell chronic lymphocytic leukemia (B-CLL) cells. In this regard, nurse-like cells (NLC), the monocyte-derived type 2 macrophages, deliver stimulatory signals via B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), and the C-X-C Motif Chemokine Ligand 12 (CXCL12). Previously, we demonstrated that brain-derived neurotrophic factor (BDNF) protects B-CLL cells from spontaneous apoptosis by activating the oncogenic complex NTSR2-TrkB (neurotensin receptor 2-tropomyosin-related kinase receptor B), only overexpressed in B-CLL cells, inducing anti-apoptotic protein Bcl-2 (B-cell lymphoma 2) expression and Src kinase survival signaling pathways. Herein, we demonstrate that BDNF belongs to the NLC secretome and promotes B-CLL survival. This was demonstrated in primary B-CLL co-cultured with their autologous NLC, compared to B-CLL cells cultured alone. Inhibition of BDNF in co-cultures, enhances B-CLL apoptosis, whereas its exogenous recombinant activates pro-survival pathways in B-CLL cultured alone (i.e. Src activation and Bcl-2 expression), at a higher level than those obtained by the exogenous recombinant cytokines BAFF, APRIL and CXCL12, the known pro-survival cytokines secreted by NLC. Together, these results showed that BDNF release from NLC trigger B-CLL survival. Blocking BDNF would support research strategies against pro-survival cytokines to limit sustained B-CLL cell survival.
Highlights
Evading apoptosis and sustained survival signaling pathways are two central hallmarks of B-cell chronic lymphocytic leukemia (B-CLL) cells
Nurse-like cells (NLC), which are type II macrophages differentiated in the presence of B-CLL cells[4], act as tumor-associated macrophages (TAMs)[5] by releasing pro-survival cytokines such as B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), and stromal cell-derived factor 1 (SDF-1) [ called CXCL12 (C-X-C Motif Chemokine Ligand 12)]4,6,7
We previously demonstrated that B-CLL survival under such conditions depends on signaling via the oncogenic complex NTSR2-tropomyosin-related kinase B (TrkB) expressed at the B-CLL cell surface[12]
Summary
Evading apoptosis and sustained survival signaling pathways are two central hallmarks of B-cell chronic lymphocytic leukemia (B-CLL) cells. We demonstrated that brain-derived neurotrophic factor (BDNF) protects B-CLL cells from spontaneous apoptosis by activating the oncogenic complex NTSR2-TrkB (neurotensin receptor 2-tropomyosin-related kinase receptor B), only overexpressed in B-CLL cells, inducing anti-apoptotic protein Bcl-2 (B-cell lymphoma 2) expression and Src kinase survival signaling pathways. Nurse-like cells (NLC), which are type II macrophages differentiated in the presence of B-CLL cells[4], act as tumor-associated macrophages (TAMs)[5] by releasing pro-survival cytokines such as B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), and stromal cell-derived factor 1 (SDF-1) [ called CXCL12 (C-X-C Motif Chemokine Ligand 12)]4,6,7 Together, these soluble factors build a microenvironment within the lymph nodes and bone marrow that promotes homing and survival of B-CLL c ells[3]. Because survival centers formed by NLC protect B-CLL cells from spontaneous apoptosis, and since NTSR2-TrkB promotes survival signals, it is tempting to speculate that BDNF is part of the NLC microenvironment and plays a crucial role in apoptosis evasion
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