Abstract 4433: Fbxw11 promotes leukemia development by activating the NF-κB signaling pathway

F-box proteins serve as the substrate recognition subunit for the SCF E3 ubiquitin ligases. These ligases ubiquitinate specifically phosphorylated substrates and play a pivotal role in the regulation of various signal transduction pathways, which, in turn, are essential for many aspects of tumorigenesis. However the role of Fbxw11 in the development of leukemia and the underlying mechanisms remain largely unknown. Here, we found two transcript variants (Fbxw11c and Fbxw11d) expressed in mouse bone marrow. More importantly, the expression of Fbxw11 in normal hematopoietic stem cells (HSCs) from Notch1-induced leukemia mice was higher than that from control mice. In order to investigate the role of Fbxw11 in leukemia, we established L1210 cell lines over-expressing Fbxw11c or Fbxw11d respectively using the lentivirus system. Over-expression of both Fbxw11 variants stimulated the proliferation of L1210 cells in vitro by cell counting and MTT assay. The tumor xenografts model with over-expression of Fbxw11c or Fbxw11d in DBA/2 mice was further established. Over-expression of both variants resulted in the increased tumor growth in vivo. Investigation of the molecular mechanism revealed that the increased cell proliferation was not due to decrease in cell apoptosis but due to increase in cell cycle. Further studies showed that overexpression of both Fbxw11c and Fbxw11d caused the activation of NF-κB signaling pathway. These findings suggest the important role of Fbxw11 in regulating the development of leukemia and indicate a potent rationale for developing Fbxw11 as a potential therapeutic target against leukemia. Citation Format: Lina Wang, Jinfeng Liao, Xiao Yang, Wenli Feng, Shayan Chen, Guoguang Zheng. Fbxw11 promotes leukemia development by activating the NF-κB signaling pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4433. doi:10.1158/1538-7445.AM2014-4433