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Mantle cell lymphoma is an aggressive subtype of non-Hodgkin’s lymphoma that claims the lives of tens of thousands of people every year. Although combination chemotherapy treatments such as CHOP have yielded promising outcomes in the clinic, the development of chemoresistance in patients has limited their long-term success. The lack of in vitro chemoresistance models has limited our ability to understand the mechanisms by which cells develop resistance, and thus our ability to develop novel therapeutics to overcome this issue. Here, we describe the development of a clinically relevant chemoresistant mantle cell lymphoma model using the JeKo-1 cell line. This was achieved through a stepwise treatment selection strategy using gradually increasing concentrations of CHOP. We show that resistant JeKo-1 cells display strong recovery and fast proliferation after treatment with an IC(50) dose of CHOP. We also found that resistant JeKo-1 cells overexpress three oncogenes implicated in the development of mantle cell lymphoma—Cyclin D1, Mcl-1, and Bcl-2—compared to normal JeKo-1 cells. We anticipate that in vitro models such as this one will enable the discovery of new therapeutic strategies for overcoming chemoresistance and improve clinical outcomes in mantle cell lymphoma patients. IMPACT STATEMENT: Mantle cell lymphoma remains one of the deadliest subtypes of non-Hodgkin’s lymphoma, in large part because patients become resistant to frontline chemotherapy. The development of strategies to treat advanced disease will be contingent upon testing in appropriate models. Most in vitro models of resistant mantle cell lymphoma are laboratory grade models that do not recapitulate the low level of chemoresistance typically observed in patients, limiting their utility. This study develops a clinically relevant in vitro model that can be used to establish the mechanisms of resistance and test new therapeutics intended to treat recurrent disease.