JNK Pathway Is Constitutively Activated and Is Required for Survival in Human Mantle-Cell Lymphoma Fresh Cells and Cell-Lines.

We previously reported that GST-pi, a cellular JNK effector and activator, was strongly expressed in MCL patient’s samples (Clin Cancer Res. 2004). Recently, several primary murine and human B lymphomas were found to constitutively express high levels of activated form of c-jun N-terminal kinase (JNK), a member of the MAP kinase family and that JNK was required for survival in these lymphoid cellular models. To our knowledge, JNK activity has not been assessed in Mantle cell lymphoma cell lines as well as MCL patient’s samples. In vitro kinase assays showed that JNK was constitutively activated in 2 EBV negative cell-lines (JEKO and UPN1) and in 5 MCL patient’s lymphoma cells. JNK and one of its major substrate ATF-2 were found to be constitutively phosphorylated in the same cell-lines and patients MCL samples. JNK inhibition by SP600125, an anthrapyrazolone pharmacological JNK inhibitor impaired cell viability (IC 50: 20 microMol), indicating that JNK exerts a major role in antiapoptotic signals in MCL JEKO and UPN1 cell-lines and fresh human MCL cells. In vitro combination showed that SP600125 and Bortezomib or cytarabine had additive effects in MCL cell-lines and patients fresh lymphoma cells. We also investigated SP600125 activity in a nude model transplanted with UPN1. SP600125 was given IP every 2 days at 40 mg/kg during 10 days, 7 days after UPN1 subcutaneous transplantation. SP600125 therapy significantly delay tumour growth in 6 mice compared to 6 mice who received vehicle alone (DMSO); p=0,001. Thus, JNK pathway activation plays a major role in MCL survival and can be an important target for future therapies.