Bortezomib: Putting mantle cell lymphoma on death row

The clinico-morphologic recognition of an intermediate form of lymphocytic lymphoma in 1992 as an entity termed Mantle Cell Lymphoma is known to be associated with the t(11:14)(q13;q32) translocation and IGH-driven overexpression of the PRAD1/ CYCLIN D1 oncogenic protein. Experimentally, however, transgenic cyclin d1 overexpression in mice is insufficient to cause lymphoma, and additional oncogenic drives are required. In murine models, c-myc has been shown to provide such a drive, but the additional drivers in human disease are less well characterised. A credible accomplice may be deregulation of proliferation in mantle cell lymphoma by loss of the cell cycle inhibitor p27 (KIP1) [1]. The level of expression of CYCLIN D1 correlates with clinical outcome in mantle cell lymphoma and may be affected by variant CYCLIN D1 isoforms as well as truncating lesions in the 30 untranslated region [2]. Clinically, elevated Ki-67, a global marker of proliferation, correlates with inferior survival outcomes in advanced mantle cell lymphoma. Despite early elucidation of the molecular pathogenesis of mantle cell lymphoma, therapeutic progress for this lymphoproliferative disorder has been far less spectacular. The importance of deregulated cell cycling in mantle cell lymphoma has led to a flurry of promising strategies directed at targeting proliferation pathways such as cell cycle inhibitors (flavopiridol) and mTOR antagonists (temsirolimus), but as highlighted by Rizatti et al. [3], agents such as bortezomib that target other cellular processes may be particularly promising. Cell-cycle escape and defective apoptosis represent a potently synergistic combination in cancer biology. Mechanisms thus far identified as perturbing cell death pathways in Mantle Cell Lymphoma include overexpression of the pro-survival protein BCL-2, homozygous deletion of the gene encoding the proapoptotic protein BIM, and reduced expression of the death receptor adaptor FADD [4], all of which favour inappropriate cell survival. Apoptosis triggered by intracellular stress is regulated by a prosurvival family of proteins including BCL-2, BCL-XL, BCL-W, MCL-1 and A1, and two proapoptotic groups of proteins: the BCL-2 Homology 3 (BH3)-only domain members, and the downstream multi-BH domain proteins BAX and BAK. The BH3-only proteins are unleashed by cell damage signals and induce BAX/BAK-mediated outer mitochondrial membrane disruption and release of caspase activators. The BH3-only proteins BID, BIM and PUMA bind and interact with all known pro-survival BCL-2 family members, whereas other BH3-only proteins target pro-survival members selectively. HRK and NOXA are the most selective, with NOXA only targeting MCL-1 [5]. Pro-survival proteins are thought to prevent apoptosis either by direct inhibition of BAX/BAK until neutralized by BH3-only proteins, or alternatively by sequestration of ‘‘activator’’ BH3-only proteins, until displaced from pro-survival proteins by other ‘‘sensitizing’’ BH3-only proteins. So-called ‘‘activator’’ BH3-only proteins, such as BIM and BID, are thought to directly target and activate BAX and BAK. There is intense interest to discover drugs capable of directly activating or mimicking the action of BH3-only proteins in tumour cells in an attempt to overcome chemoresistance. The current work by Rizatti et al. [3] supports earlier observations that bortezomib increases pro-apoptotic targeting of