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Pathogenesis of Mantle-Cell Lymphoma: All Oncogenic Roads Lead to Dysregulation of Cell Cycle and DNA Damage Response Pathways

Veronica Fernàndez, Elena Hartmann, German Ott, Elias Campo, Andreas Rosenwald

From the Hematopathology Section, Laboratory of Pathology, Hospital Clinic, University of Barcelona, Spain; and the Institute of Pathology, University of Würzburg, Germany

Address reprint requests to Andreas Rosenwald, MD, Institute of Pathology, University of Würzburg, Josef-Schneider-Str 2, Würzburg, 97080 Germany; e-mail: rosenwald{at}mail.uni-wuerzburg.de.

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.

Supported by the Interdisciplinary Center for Clinical Research (IZKF) at the University of Würzburg, Germany (A.R.), the Spanish Ministery of Education and Science (SAF 02/3261, E.C.) and by the European Grant No. 503351, European Mantle Cell Lymphoma Network: Translational Determination of Molecular Prognostic Factors (A.R., E.C., G.O.).

V.F. and E.H. contributed equally to this work.

E.C. and A.R. should be considered co-senior authors.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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