This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fernàndez, V. Articles by Rosenwald, A. Search for Related Content PubMed PubMed Citation Articles by Fernàndez, V. Articles by Rosenwald, A.

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.

This article has been cited by other articles:

				S. Sander, L. Bullinger, E. Leupolt, A. Benner, D. Kienle, T. Katzenberger, J. Kalla, G. Ott, H. K. Muller-Hermelink, T. F.E. Barth, et al. Genomic aberrations in mantle cell lymphoma detected by interphase fluorescence in situ hybridization. Incidence and clinicopathological correlations Haematologica, May 1, 2008; 93(5): 680 - 687. [Abstract] [Full Text] [PDF]

				H. Li, X. Ma, J. Wang, J. Koontz, M. Nucci, and J. Sklar Effects of rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell proliferation and survival PNAS, December 11, 2007; 104(50): 20001 - 20006. [Abstract] [Full Text] [PDF]

				N. Kawamata, J. Chen, and H. P. Koeffler Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells Blood, October 1, 2007; 110(7): 2667 - 2673. [Abstract] [Full Text] [PDF]

				D. Kienle, T. Katzenberger, G. Ott, D. Saupe, A. Benner, H. Kohlhammer, T. F.E. Barth, S. Holler, J. Kalla, A. Rosenwald, et al. Quantitative Gene Expression Deregulation in Mantle-Cell Lymphoma: Correlation With Clinical and Biologic Factors J. Clin. Oncol., July 1, 2007; 25(19): 2770 - 2777. [Abstract] [Full Text] [PDF]

				M. Pinyol, S. Bea, L. Pla, V. Ribrag, J. Bosq, A. Rosenwald, E. Campo, and P. Jares Inactivation of RB1 in mantle-cell lymphoma detected by nonsense-mediated mRNA decay pathway inhibition and microarray analysis Blood, June 15, 2007; 109(12): 5422 - 5429. [Abstract] [Full Text] [PDF]

				S. H. Peterson, D. T. Nardelli, T. F. Warner, S. M. Callister, J. R. Torrealba, and R. F. Schell Anti-p19 Antibody Treatment Exacerbates Lyme Arthritis and Enhances Borreliacidal Activity Clin. Vaccine Immunol., May 1, 2007; 14(5): 510 - 517. [Abstract] [Full Text] [PDF]

				E. Hartmann, V. Fernandez, H. Stoecklein, L. Hernandez, E. Campo, and A. Rosenwald Increased MDM2 expression is associated with inferior survival in mantle cell lymphoma, but not related to the MDM2 SNP309 Haematologica, April 1, 2007; 92(4): 574 - 575. [Abstract] [Full Text] [PDF]

				I. Salaverria, A. Zettl, S. Bea, V. Moreno, J. Valls, E. Hartmann, G. Ott, G. Wright, A. Lopez-Guillermo, W. C. Chan, et al. Specific Secondary Genetic Alterations in Mantle Cell Lymphoma Provide Prognostic Information Independent of the Gene Expression-Based Proliferation Signature J. Clin. Oncol., April 1, 2007; 25(10): 1216 - 1222. [Abstract] [Full Text] [PDF]

				S. Marce, O. Balague, L. Colomo, A. Martinez, S. Holler, N. Villamor, F. Bosch, G. Ott, A. Rosenwald, L. Leoni, et al. Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival: implications for a potential targeted therapy. Clin. Cancer Res., June 15, 2006; 12(12): 3754 - 3761. [Abstract] [Full Text] [PDF]

				T. Katzenberger, C. Petzoldt, S. Holler, U. Mader, J. Kalla, P. Adam, M. M. Ott, H. K. Muller-Hermelink, A. Rosenwald, and G. Ott The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma Blood, April 15, 2006; 107(8): 3407 - 3407. [Full Text] [PDF]