title: Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways.
abstract: 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.
authors.affiliation: Institute of Pathology, University of Würzburg, Josef-Schneider-Str 2, Würzburg, 97080 Germany.
authors.forename: Veronica
authors.initials: V
authors.lastname: Fernàndez
authors.forename: Elena
authors.initials: E
authors.lastname: Hartmann
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
mesh_terms: D002453:Cell Cycle / Q000235:genetics* / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004249:DNA Damage / Q000235:genetics* / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D015513:Oncogene Proteins; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases