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Blood, 1 January 2007, Vol. 109, No. 1, pp. 331-338.
Prepublished online as a Blood First Edition Paper on September 5, 2006; DOI 10.1182/blood-2006-02-001800.
 Previous Article | Next Article 
Submitted February 3, 2006
Accepted June 28, 2006
Neutrophil-derived APRIL concentrated in tumor lesions
by proteoglycans correlates with human B cell Lymphoma
aggressiveness
Juerg Schwaller, Pascal Schneider, Paulette Mhawech-Fauceglia, Thomas McKee, Samir Myit, Thomas Matthes, Jurg Tschopp, Olivier Donze, Frederique-Anne Legal, and Bertrand Huard*
Department of Research, University Hospital, Basel, Switzerland
Department of Biochemistry, University of Lausanne, Switzerland
Roswell Park Cancer Institute, Buffalo, NY
Department of Pathology, University Medical Center, Geneva, Switzerland
Hematology Unit, Department of Internal Medicine, University Hospital, Geneva, Switzerland
Apotech Corp., Epalinges, Switzerland
Department of Dermatology, University Hospital, Geneva, Switzerland
Louis Jeantet Laboratory, University Medical Center and Hospital, Geneva, Switzerland
* Corresponding author; email: bertrand.huard{at}medecine.unige.ch.
A Proliferation Inducing TNF Ligand (APRIL) co-stimulates B-cell activation. When over-expressed in mice, APRIL induces B-cell neoplasia, reminiscent of human B-cell chronic lymphoid (B-CLL) leukemia. We analyzed APRIL expression in situ in human Non-Hodgkin Lymphomas. APRIL up-regulation was only observed in high-grade B-cell lymphomas, Diffuse Large B-cell Lymphoma (DLBCL) and Burkitt Lymphoma (BL). Up-regulation was seen in 46% and 20% of DLBCL and BL respectively. In DLBCL, neutrophils, constitutively producing APRIL and infiltrating the tumor tissue, were the main cellular source of APRIL. Rare DLBCL cases showed a predominance of histiocytes or mesenchymal cells as APRIL source. APRIL secreted by neutrophils accumulated on tumor cells via proteoglycan binding. In addition to proteoglycans, DLBCL tumor cells expressed the APRIL signaling receptor, TACI and/or BCMA, indicating that these tumor cells are fully equipped to respond to APRIL. A retrospective clinical analysis revealed a significant correlation between high expression of APRIL in tumor lesions and decreased overall patient survival rate. Hence, APRIL produced by inflammatory cells infiltrating lymphoma lesions may increase tumor aggressiveness and affect disease outcome.
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