Mantle-cell lymphoma (MCL) is a well-defined subtype of B-cell non-Hodgkin's 
lymphomas (B-NHL), accounts for approximately 6% of all lymphoid neoplasms, and 
has a median survival of 3 to 4 years. The genetic hallmark of MCL is the 
chromosomal translocation t(11;14)(q13;q32) that leads to deregulation and 
upregulation of Cyclin D1, an important regulator of the G1 phase of the cell 
cycle. This genetic event is present in virtually all cases of MCL, whereas 
additional genetic alterations that occur in subsets of MCL have been described. 
Most of these alterations appear to disturb the cell cycle machinery/interfere 
with the cellular response to DNA damage, thus making MCL a paradigm for cell 
cycle and DNA damage response dysregulation in cancer in general. In particular, 
Cyclin D1 upregulation, genomic amplification of the cyclin-dependent kinase 
(CDK) -4, deletions of the CDK inhibitor p16(INK4a) and overexpression of BMI-1, 
a transcriptional repressor of the p16(INK4a) locus, are associated with 
dysregulation of the cell cycle machinery in MCL. The DNA damage response 
pathway is affected by frequent alterations of the ataxia-telangiectasia mutated 
(ATM) kinase as well as occasional inactivation of checkpoint kinase (CHK)-1 and 
CHK2 that are kinases that act downstream of ATM in response to detection of DNA 
damage. Moreover, p53 is frequently targeted by alterations in MCL. A recent 
gene expression profiling study defined the proliferation signature, a 
quantitative measure of gene expression of proliferation-associated genes as the 
strongest survival predictor available to date allowing the definition of 
prognostic MCL subgroups that differ in median survival by more than 5 years.