Targeted therapies in mantle cell lymphoma

Mantle cell lymphoma (MCL) is characterized by the presence of the t(11 ;14)(g13 ;g32) translocation which results in cyclin Dl over-expression. MCL is one of the most difficult lymphoproliferative disorders to manage with a median survival rate of 43 months from diagnosis. The poor prognosis associated with MCL is due in large part to its late classification as a separate clinical entity leading to a dearth in available pre-clinical models. The specific objectives of the research described in this thesis were (1) to establish MCL preclinical models of disease and (2) to evaluate deregulated cell signaling pathways in MCL that can impact treatment response. Pre-clinical models of MCL were established from pre-existing cell lines containing the t(11 ;14)(g13 ;g32). These cell lines were previously misclassified because they were developed prior to the classification of MCL as a distinct lymphoma subtype. With the establishment of MCL models, deregulated cell signaling pathways in MCL and response to different treatment strategies were investigated. These included an investigation of the cell signaling pathways activated in bcl-2 over-expressing MCL cells that were treated with oblimersen; a molecular gene silencing strategy that effectively suppresses bcl-2 in vitro and in vivo. Silencing bcl-2 provided insight into which pathways were influenced by bcl-2 over-expression in MCL. More specifically loss of cyclin D1, NF-KB, p53, bax and p27 were observed following bcl-2 silencing. Additional studies investigated how abnormal expression of CD40/CD40L and Fas/FasL along with bcl-2 family members contributes to B cell clonal expansion and influences Rituximab-mediated cell death in MCL models. Rituximab is a chimeric monoclonal antibody targeted against B cells and both Rituximab-sensitive and insensitive MCL models were defined. An abnormally high expression of bcl-2, bcl-x L, mcl-1, CD40/CD40L and Fas were observed in all MCL cells, as well as high levels of soluble FasL, capable of blocking Fas-mediated apoptosis. ...