3200 – using quantitative proteomics to identify new therapeutic targets in mantle cell lymphoma

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma that affects 4-6% of the population. Despite the relatively low incidence of MCL compared to other lymphomas, MCL only has a 5-year survival rate of 50%, making it one of the most deadly. While 90% of patients exhibit the t(11;14) translocation resulting in overexpression of the cell cycle regulatory protein CyclinD1 (CCND1), this alone is not enough for disease initiation. Patients must also have secondary mutations for disease manifestation; however, the number and variety of these mutations differ between every patient. This genetic complexity lends to the difficulty in disease treatment, and there are no standard therapies currently available. Although some therapies have shown promise for treatment in the early stages of the disease, all cases eventually stop responding, resulting in relapse. As such, it is imperative that new therapies be identified to treat this deadly disease. To this end, our lab performed quantitative proteomics on B cells from five healthy donors and tumors from different lymphoma patients including sixteen MCL, seven follicular lymphoma, and seven chronic lymphocytic lymphoma in order to identify changes at the proteomic level that are specific to MCL. This analysis has identified eight proteins that are specifically upregulated in MCL but are unchanged transcriptionally and would have gone unidentified by typical patient screening methods. Dysregulation of one of these proteins, HMGB3, has been shown to lend drug resistance in ovarian cancer and poor prognosis in neuroblastoma; however, has never been associated with MCL. Knockdown of HMGB3 in MCL cell lines results in reduced proliferation, increased apoptosis, and alterations to cell cycle, indicating it may prove to be a potential therapeutic target for MCL treatment. Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma that affects 4-6% of the population. Despite the relatively low incidence of MCL compared to other lymphomas, MCL only has a 5-year survival rate of 50%, making it one of the most deadly. While 90% of patients exhibit the t(11;14) translocation resulting in overexpression of the cell cycle regulatory protein CyclinD1 (CCND1), this alone is not enough for disease initiation. Patients must also have secondary mutations for disease manifestation; however, the number and variety of these mutations differ between every patient. This genetic complexity lends to the difficulty in disease treatment, and there are no standard therapies currently available. Although some therapies have shown promise for treatment in the early stages of the disease, all cases eventually stop responding, resulting in relapse. As such, it is imperative that new therapies be identified to treat this deadly disease. To this end, our lab performed quantitative proteomics on B cells from five healthy donors and tumors from different lymphoma patients including sixteen MCL, seven follicular lymphoma, and seven chronic lymphocytic lymphoma in order to identify changes at the proteomic level that are specific to MCL. This analysis has identified eight proteins that are specifically upregulated in MCL but are unchanged transcriptionally and would have gone unidentified by typical patient screening methods. Dysregulation of one of these proteins, HMGB3, has been shown to lend drug resistance in ovarian cancer and poor prognosis in neuroblastoma; however, has never been associated with MCL. Knockdown of HMGB3 in MCL cell lines results in reduced proliferation, increased apoptosis, and alterations to cell cycle, indicating it may prove to be a potential therapeutic target for MCL treatment.