BDNF belongs to the nurse-like cell secretome and supports survival of B chronic lymphocytic leukemia cells

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.

Nurse-Like Cells and Chronic Lymphocytic Leukemia B Cells: A Mutualistic Crosstalk inside Tissue Microenvironments

“…The stimulation of these receptors induces the activation of NF-κB pathway and the expression of Bcl-2, preserving CLL cells’ survival [ 54 ]. In the same line, brain-derived neurotrophic factor (BDNF), secreted by NLC, activates the complex NTSR2-TrkB expressed at the CLL cells’ surface, inducing Src pro-survival signal and the expression of Bcl-2 [ 55 ]. Again, NLC release galectin 1 (Gal1) into the surrounding environment.…”

IL-10 Rescues CLL Survival through Repolarization of Inflammatory Nurse-like Cells

“…NLC expressing CD68, CD163, and CD206 are found in all tumoral niches [ 8 , 9 , 10 ]. They form a survival support for CLL cells, mediated by cell contacts involving different surface molecules such as LFA-3 or galectin-1 [ 7 , 11 , 12 ] and, controversially, CD31 [ 13 , 14 , 15 ]. Moreover, NLC produce pro-survival soluble factors, such as: BAFF, APRIL, SDF-1 (CXCL12), or BDNF [ 16 , 17 ], and can also stimulate the release of CCL3 and CCL4 by leukemic cells to further strengthen TME [ 18 ].…”

Clinical Proteomics of Biofluids in Haematological Malignancies

“…In primary effusion lymphoma (PEL), proteomic analysis of PEL cell secretome identified a number of proteins associated with growth and the immune response, which may represent potential biomarker candidates [ 144 ]. In B chronic lymphocytic leukemia (B-CLL), a nurse-like cell secretory protein, brain-derived neurotrophic factor (BDNF), was found to support the survival of B-CLL cells [ 145 ]. These studies demonstrate the myriad of secretory factors from malignant blood cells and neighbouring cells which influence the pathobiology of haematological malignancies, illustrating cancer tissue–proximal fluids and conditioned media as potential sources of biomarker discovery and therapeutic target detection.…”