SMOC-2 suppression in diffuse large B-cell lymphoma may confer resistance to rituximab
MetadataShow full item record
Rituximab is a genetically constructed chimeric mouse-human monoclonal IgG1 kappa antibody that recognizes the CD20 antigen. It has been the top selling oncology drug for nearly a decade. Rituximab was approved for medical use in 1997 and since then, it has improved outcomes in all B-cell malignancies. However, about 40% of patients relapse after initially responding to rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). It is therefore important to understand any potential mechanisms of resistance in order to improve patient survival through better therapeutic choices. Since rituximab’s mechanisms of action are challenging to study in non-human models, our group used in vitro studies linking genotype to phenotype via Genome-Wide Association study (GWAS) and identified a Single Nucleotide Polymorphism (SNP) in SMOC-2, which encodes an extracellular matrix protein, that might be involved in rituximab sensitivity. In order to determine whether the expression of SMOC-2 affects rituximab sensitivity, malignant B cells with a SMOC-2 knockdown were tested in an in vitro Complement Dependent Cytotoxicity (CDC) rituximab killing assay. After performing CDC assays on several Diffuse Large B-Cell Lymphoma (DLBCL) SMOC-2 knockdown cell lines, the HBL-1 cell line exhibited resistance to rituximab. However, western blot analysis yielded inconclusive evidence about the knockdown of SMOC-2, since the SMOC-2 band could not be confidently identified. Understanding the mechanisms of intrinsic and acquired resistance to drugs in cancer therapy may enable the use of patient genotypes to determine which anti-CD20 would be most effective or allow interventions to restore rituximab sensitivity in patients.
Biological sciences honors program; Rituximab Resistance; Lymphoma; SMOC-2; Extracellular Matrix; CD20; GWAS; CDC; RNAi; CRISPR
B.S., Biological Sciences
Bachelor of Science
dissertation or thesis