Proapoptotic protein BIM as a novel prognostic marker in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma. Numerous studies have demonstrated many genetic aberrations in MCL in addition to the characteristic t(11:14), including frequent biallelic deletions of Bim, a proapoptotic member of the BCL-2 family. In mice, Bim deletion coupled with cyclin D1 overexpression generates pathologic and molecular features of human MCL. Since the regulation of apoptosis is crucial in MCL pathogenesis, we hypothesize that BIM expression may be associated with tumor cell survival. Clinical data and tissue from 100 nodal MCL cases between 1988 and 2009 were collected from three large academic medical centers. The average patient age of our MCL cohort was 65.5 years old (range, 42-97) with a 2:1 male to female ratio. Immunohistochemistry was performed with a validated anti-BIM antibody. Patients were separated into low and high BIM-expressing categories with a cutoff of 80%. As expected for a proapoptotic tumor suppressor, patients with high BIM expression were less likely to have progressive disease and more likely to have a complete response (P = .022). In addition, high BIM-expressing MCL tumors revealed a trend toward increased overall survival with this trend persisting in sub-analysis of Ann Arbor stages III and IV. No correlation between BIM expression, Ki-67 index, and MIPI score was observed, suggesting a role for BIM as a novel independent prognostic factor. While BIM is only one member of a complex family of apoptosis-regulating proteins, these findings may yield clinically relevant information for the prognosis and therapeutic susceptibility of MCL.