| Abstract: | Background: We have recently uncovered that BAFF expression is closely associated with H. pylori-independent growth of gastric MALT lymphoma (Blood 2008;112:2927-34). mTOR inhibitor has recently emerged as an important new class of drugs that are active in the treatment of lymphoma. In this study, we sought to examine whether RAD001, an mTOR inhibitor, can be effective in the treatment of H. pylori-independent gastric MALT lymphoma. Methods: The primary MALT lymphoma cell was obtained from fresh marrow aspiration-derived lymphoma tissues of a t(11;18)(q21;q21)- and t(1;14)(p22;q32)- negative H. pylori-independent gastric MALT lymphoma patient who had failed chemotherapy. The cell cycle phase was analyzed by flow cytometry. Expression of pAKT (Ser473 and Thr308), p-p70S6K, p-4E-BP1, p-mTOR, p-eIF4E, cyclin A, cyclin D3, BCL10, BCL3, NF-\#954;B (p65), c-Myc, and insulin receptor substrate-1 (IRS-1), and BAFF was measured by immunoblotting. Transactivity of NF-\#954;B was measured by electromobility shift assay. Results: RAD001 blocked cell cycle progression in G0/G1 phase and induced no significant apoptosis in MALT lymphoma cell line with the IC50s of growth suppression less than 50 nM. In parallel with the RAD001-induced growth inhibition, a dose- and schedule- dependent down-regulation of pAKT (Ser473 and Thr308), p-mTOR, p-p70S6K, p-4E-BP1, p-eIF4E, cyclin A, and cyclin D3 was demonstrated. Furthermore, RAD001 also suppressed the expression of c-Myc, TNF-\#945;, and BAFF, and nuclear expression of BCL3 and BCL10, and NF-\#954;B transactivity, but did not affect IRS-1. Conclusions: RAD001 is effective in growth suppression of a H. pylori-independent gastric MALT lymphoma cell line, and the activity is at least partly related to down-regulation of pAKT, mTOR, eIF4E, and BAFF/BCL10/NF-\#954;B signaling pathways. |
