AUY922 effectively targets against activated B cell subtype of diffuse large B-cell lymphoma and low-grade lymphoma cells harboring genetic alteration-associated nuclear factor-κB activation

Hui-Jen Tsaiabcd, Neng-Yao Shiha, Sung-Hsin Kuoe, Ann-Lii Chenge, Hui-You Lina, Tsai-Yun Chenb, Kung-Chao Changf, Sheng-Fung Linc, Jeffrey S. Changa & Li-Tzong Chenabgh*a National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwanb Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwanc Division of Hematology/Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwand Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwane Department of Oncology, National Taiwan University Hospital, Taipei, Taiwanf Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwang Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwanh Institute of Molecular Medicine, National Cheng Kung University, Tainan, TaiwanCorrespondence: Dr. Li-Tzong Chen, 2F No 367, Sheng-Li Road, Tainan 70456, Taiwan R.O.C. Tel: 886-6-208-3422, ext. 65110. Fax: 886-6-208-3427. E-mail: leochen@nhri.org.twRecurrent genetic alterations that are frequently observed in some low-grade lymphomas, such as activated B cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL) and mucosa-associated lymphoid tissue type lymphoma (MALT lymphoma) are usually associated with nuclear factor-κB (NF-κB) activation and confer resistance to therapy. In this study, we investigated the therapeutic efficacy and molecular mechanisms of AUY922, a novel Hsp90 inhibitor, in representative cell lines OCI-Ly3 (ABC-DLBCL) and MA-1 (a low-grade lymphoma cell line with t(14;18)/IgH-MALT1translocation) to explore its potential use in the treatment of refractory B-cell lymphoma. Our results showed that AUY922 effectively induced growth inhibition and apoptosis of OCI-Ly3 and MA-1 cells, which were accompanied by down-regulation of the expression levels of NF-κB and Bcl-2 family proteins, as well as molecules of multiple signaling pathways involving cell proliferation, growth and survival. The growth inhibitory effect of AUY922 was further confirmed in a mouse xenograft model. These findings indicate the potential use of AUY922 in B cell lymphomas.