Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma (NHL) which is one of the most aggressive lymphomas. Despite recent improvements in therapies, the development of therapy-resistance is still a major problem; therefore, in order to understand the molecular basis of therapy-resistance, stable therapy-resistant MCL cell lines have been established by us. Based on the gene expression profiles of these cell lines, Polo-like kinase 1 (PLK1) was chosen as a therapeutic target. In this paper, we demonstrate a significant antilymphoma effect of targeting PLK1 in therapy-resistant MCL cells and primary MCL cells from refractory patients. PLK1 knockdown with the antisense oligonucleotide (ASO)/or small molecule inhibitor BI2536 showed significantly decreased proliferation and increased apoptosis in therapy-resistant MCL cell lines and MCL primary cells. Additionally, the direct protein-protein interaction partners of PLK1 were mapped using ingenuity pathway and confirmed the level of association of these partners with PLK1 based on their expression changes following PLK1 knockdown using real-time PCR. Results suggest that PLK1 is a viable target for the treatment of therapy-resistant MCL. 1. Introduction Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin lymphoma. MCL is typically diagnosed at late stage, predominantly in elderly males and commonly metastasizes to multiple sites including the liver, kidney, gastrointestinal tract, or bone marrow [1, 2]. Cytogenetically, the majority of MCL patients have a t(11;14)(q13;q32) which deregulates cyclin D1 (CCND1) and immunoglobulin heavy chain (IGH), resulting in overexpression of CCND1 and increased proliferation [3, 4]. While the median overall survival has improved to around seven years with the advancements in therapies, the recurrence due to therapy-resistance is still a major problem in refractory MCL. Combination chemotherapy regimens like CHOP combined with rituximab are common and frontline responses are generally good, but the development of therapy-resistance precludes long-term survival [5–7]. Additional options include high-dose therapy followed by hematopoietic stem cell transplantations and targeted treatments such as bortezomib, lenalidomide, or temsirolimus. However, the resistance ultimately arises even with second-line therapies [8–10]. Therefore, it would be beneficial to identify the molecular mechanisms of therapy-resistance in MCL and develop a more specific targeted genetic approach to overcome the problem. As previously described, our lab has generated
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