Date of Graduation
Doctor of Philosophy (PhD)
Nami McCarty, Ph.D.
Zhiqiang An, Ph.D.
R. Eric Davis, M.D.
Shiaw-Yih Lin, Ph.D.
Timothy J. McDonnell, M.D., Ph.D.
Although PAX5 conditional silencing in mice models led to aggressive lymphoma formation, there has been a lack of understanding in the precise functions of PAX5 in human B cell cancers. PAX5 expression is used to diagnose different B cell lymphoma in the clinic including mantle cell lymphoma (MCL), which is one of the most aggressive B cell cancers. PAX5 levels in MCL patients were significantly repressed compared to normal B cells. Surprisingly, we found there were quantitative differences in PAX5 expression levels within MCL patient tissues, which prompted us to silence PAX5 in MCL cell lines to characterize PAX5 functions in MCL disease progression. PAX5 silencing in MCL cells (PAX5–) not only increased cell proliferation in vitro and in vivo but also contributed towards retention of quiescent PKH+ stem-like cells in xenograft bones. Decreased PAX5 signaling led to deregulation of the cell cycle and increased MCL survival pathways. PAX5– cells also exhibited increased dissemination and adhesion to bone marrow stromal cells. Analyses of clinical MCL cases further revealed that lower PAX5 levels are correlated with MCL dispersal and poorer overall survival in patients. In addition, aggressive blastoid variant MCL demonstrated lower levels of PAX5 compared to non-blastoid types, indicating a decreased PAX5 phenotype promotes MCL dispersal and progression. We also conducted a high throughput screening (HTS) of 3800 compounds to discover compounds that selectively target the aggressive MCL. The data revealed important properties of PAX5– MCL cells, which are highly drug resistant compared to parental cells. Several novel compounds were discovered through the HTS, which can be new potential therapeutic options for aggressive MCL. Collectively, our data support PAX5 functions as a tumor suppressor-like protein in MCL, and that PAX5 expression can predict advanced MCL patient prognosis.
PAX5, Mantle Cell Lymphoma, High Throughput Screening