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.
These deregulated pathways were associated with response to Rituximab treatment in a
sensitive MCL model. These studies demonstrated some of the key pathways associated
with treatment response in MCL, and the establishment of well characterized MCL
models enables us to continue to explore new treatment strategies currently being studied
in other lymphomas.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:BVAU.2429/922 |
| Date | 05 1900 |
| Creators | Tucker, Catherine Amanda |
| Publisher | University of British Columbia |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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