The role of BCL3 in high risk plasma cell myeloma
Multiple myeloma (MM), a chronic and incurable plasma cell malignancy, accounts for approximately 2% of all cancer deaths worldwide. The median age of disease onset is approximately 65 years, with an average life expectancy of approximately 7-8 years from the time of diagnosis. However, about 20% of patients at diagnosis have a median survival of <2 years. These individuals are referred to as “ultra high-risk” MM patients. While most patients with MM respond to therapy, “ultra high-risk” MM patients respond poorly to therapeutic regimens, including the novel agents, thus highlighting the need to understand the underlying molecular mechanisms that of this disease subgroup. High BCL3 expression, an NF-κB co-activator, has been purported to be a feature of proliferative MM; often associated with a poor prognosis.
Previous observations made by our laboratory using an independent patient cohort recapitulate these findings, demonstrating that patients with elevated BCL3 expression have inferior progression free survival (PFS) and overall survival (OS). Despite this striking clinical observation, the biological consequences of BCL3 expression in MM remain poorly understood. For this reason, we are interested in (i) determining whether high levels of Bcl-3 could be used as a biomarker to identify ultra high-risk MM; (ii) establishing the mechanism of Bcl-3 upregulation in MM, and (iii) understanding the functional consequence of Bcl-3 upregulation in MM. Research of this nature is feasible in human MM cell lines, as we can alter levels of BCL3 across various cell lines and observe the impact this has on MM cell proliferation and survival. We will utilise the CRISPR/Cas9 methodology to edit the BCL3 gene in myeloma cell lines in an inducible manner. To complement these experiments, we will also overexpress Bcl-3 in cell lines that express low levels of Bcl-3 and assess cell growth and proliferation.
Dr Pasquale Fedele
Dr Michael Low
Dr Raffi Gugasyan