STAT5 Signaling Is Associated with the Outcome of Follicular and Mantle Cell Lymphoma Patients Treated with Immunochemotherapy.

Addition of rituximab (R) to chemotherapy (immunochemotherapy) has significantly improved the outcome of B-cell lymphoma patients. However, responses are still unpredictable due to heterogeneous nature of these diseases. The aim of this study was to determine if differences in gene expression in follicular lymphoma (FL) and mantle cell lymphoma (MCL) tissue correlate with outcome in response to immunochemotherapy. 24 FL and 15 MCL patients were classified into complete (CR) or other responders after immunochemotherapy, and genes capable of separating the groups were identified using oligonucleotide-based microarray and supervised learning technique. One of the transcripts associated with increased CR rates in FL was signal transducer and activator of transcription 5a (STAT5a), a transcription factor and a mediator of cellular responses after cytokine stimulation. According to Kaplan Meier estimates, high STAT5a mRNA levels were associated with better progression free survival (PFS). Immunohistochemical analyses of FL samples demonstrated that predominant STAT5a activity localized to resident T-lymphocytes but only 20% of the samples were STAT5a positive. In a validation set of 79 FL patients, a better PFS was observed among patients with high STAT5a protein expression. In contrast, high STAT5a mRNA and protein levels were associated with poor outcome in MCL patients. In the MCL tissue, STAT5a expression localized to nonmalignant T-lymphocytes but also to tumor cells. In comparison to FL, T-lymphocytes were more uniformly positive for STAT5a. In sum, the data show that nonmalignant tumor cells have a profound prognostic impact both in FL and MCL, but also suggest that depending on the lymphoma subtype, the activity of a certain signaling pathway can have either positive or negative consequences on the survival of immunochemotherapy-treated lymphoma patients.