Prognostic Significance of BAD and AIF Apoptotic Pathways in Diffuse Large B-Cell Lymphoma

Background:To determine whether proapoptotic proteins were associated with clinicopathologic heterogeneity and influenced survival in patients with diffuse large B-cell lymphoma (DLBCL), we evaluated patterns of expression of the BCL-2 family member BAD, PP1α (the catalytic subunit of PP1 involved in activation of BAD), and apoptosis-inducing factor (AIF).Patients and Methods:We retrospectively analyzed 46 patients all treated with standard chemotherapy ([CHOP] cyclophosphamide/doxorubicin/vincristine/prednisone–like); of these, 16 received rituximab. Immunohistochemical analyses were performed from biopsy samples of nodal DLBCL that were performed at initial diagnosis. Normal reactive lymph nodes were used as controls.Results:BAD expression was found in 38 of 46 DLBCL cases and, though variable, was often strong. PP1α and AIF were detected in all tumors tested with a relative strong expression. Lower BAD expression was shown to be significantly associated with advanced clinical stages (Ann Arbor stage III + IV and International Prognostic Index intermediate-high to high; P = .006 and P = .0008, respectively). Moreover, BAD staining was positively correlated with BCL-2 (P = .022) and PP1α (P = .013) staining. Finally, high AIF expression proved to be predictive of a longer overall survival in non–rituximab-treated patients.Conclusion:Our study shows for the first time in DLBCL that differential BAD expression might play a role in the development of the disease, possibly reflecting its function as a tumor suppressor. Furthermore, our data highlight the interest in targeting BAD phosphatases and AIF-mediated mitochondrial apoptosis for new therapeutic strategies.