title: Macrophage-mediated chronic lymphocytic leukemia cell survival is independent of APRIL signaling.
abstract: Survival of chronic lymphocytic leukemia (CLL) cells is mainly driven by interactions within the lymph node (LN) microenvironment with bystander cells such as T cells or cells from the monocytic lineage. Although the survival effect by T cells is largely governed by the TNFR ligand family member CD40L, the exact mechanism of monocyte-derived cell-induced survival is not known. An important role has been attributed to the TNFR ligand, a proliferation-inducing ligand (APRIL), although the exact mechanism remained unclear. Since we detected that APRIL was expressed by CD68+ cells in CLL LN, we addressed its relevance in various aspects of CLL biology, using a novel APRIL overexpressing co-culture system, recombinant APRIL, and APRIL reporter cells. Unexpectedly, we found, that in these various systems, APRIL had no effect on survival of CLL cells, and activation of NF-κB was not enhanced on APRIL stimulation. Moreover, APRIL stity mulation did not affect CLL proliferation, neither as single stimulus nor in combination with known CLL proliferation stimuli. Furthermore, the survival effect conveyed by macrophages to CLL cells was not affected by transmembrane activator and CAML interactor-Fc, an APRIL decoy receptor. We conclude that the direct role ascribed to APRIL in CLL cell survival might be overestimated due to application of supraphysiological levels of recombinant APRIL.
authors.affiliation: Academic Medical Center, Department of Hematology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Academic Medical Center, Department of Experimental Immunology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Mha
authors.initials: M
authors.lastname: van Attekum
authors.affiliation: Academic Medical Center, Department of Hematology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Academic Medical Center, Department of Experimental Immunology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Terpstra
authors.affiliation: Academic Medical Center, Department of Hematology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Academic Medical Center, Department of Experimental Immunology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Reinen
authors.affiliation: Academic Medical Center, Department of Hematology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: A P
authors.initials: AP
authors.lastname: Kater
authors.affiliation: Academic Medical Center, Department of Experimental Immunology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Eldering