1. ¹Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada
2. ²Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence: Dr R Lai, Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2. E-mail: raymondl@cancerboard.ab.ca

Received 21 October 2008; Revised 19 February 2009; Accepted 30 March 2009; Published online 4 June 2009.

Abstract

Interleukin-21 (IL-21) has been recently shown to modulate the growth of specific types of B-cell neoplasm. Here, we studied the biological effects of IL-21 in mantle cell lymphoma (MCL). All MCL cell lines and tumors examined expressed the IL-21 receptor. Addition of recombinant IL-21 (rIL-21) in vitro effectively induced STAT1 activation and apoptosis in MCL cells. As STAT1 is known to have tumor-suppressor functions, we hypothesized that STAT1 is important in mediating IL-21-induced apoptosis in MCL cells. In support of this hypothesis, inhibition of STAT1 expression using siRNA significantly decreased the apoptotic responses induced by IL-21. To further investigate the mechanism of IL-21-mediated apoptosis, we employed oligonucleotide arrays to evaluate changes in the expression of apoptosis-related genes induced by rIL-21; rIL-21 significantly upregulated three proapoptotic proteins (BIK, NIP3 and HARAKIRI) and downregulated two antiapoptotic proteins (BCL-2 and BCL-XL/S) as well as tumor necrosis factor-. Using an ELISA-based assay, we demonstrated that rIL-21 significantly decreased the DNA binding of nuclear factor-B, a transcriptional factor known to be a survival signal for MCL cells. To conclude, IL-21 can effectively induce apoptosis in MCL via a STAT1-dependent pathway. Further understanding of IL-21-mediated apoptosis in MCL may be useful in designing novel therapeutic approaches for this disease.