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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4599-4606. Prepublished online as a Blood First Edition Paper on February 13, 2007; DOI 10.1182/blood-2006-08-039859. This Article Full Text (PDF) Supplemental Appendix All Versions of this Article: blood-2006-08-039859v1 109/11/4599    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wiestner, A. Articles by Staudt, L. M Search for Related Content PubMed PubMed Citation Articles by Wiestner, A. Articles by Staudt, L. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 7, 2006 Accepted January 23, 2007 Point mutations and genomic deletions in Cyclin D1 create stable truncated mRNAs that are associated with increased proliferation rate and shorter survival in mantle cell lymphoma Adrian Wiestner, Mahsa Tehrani, Michael Chiorazzi, George Wright, Federica Gibellini, Kazutaka Nakayama, Hui Liu, Andreas Rosenwald, H. Konrad Muller-Hermelink, German Ott, Wing C Chan, Timothy C Greiner, Dennis D Weisenburger, Julie M Vose, James O Armitage, Randy D Gascoyne, Joseph M Connors, Elias Campo, Emilio Montserrat, Francesc Bosch, Erlend B Smeland, Stein Kvaloy, Harald Holte, Jan Delabie, Richard I Fisher, Thomas M Grogan, Thomas P Miller, Wyndham H Wilson, Elaine S Jaffe, and Louis M Staudt* CCR, National Cancer Institute, NIH, Bethesda, MD, United States HB, NHLBI, NIH, Bethesda, MD, United States University of Wurzburg, Wurzburg, Germany University of Nebraska Medical Center, Omaha, NE, United States British Columbia Cancer Agency, Vancouver, British Columbia, Canada Hospital Clinic, University of Barcelona, Barcelona, Spain Norwegian Radium Hospital, Oslo, Norway Southwest Oncology Group, San Antonio, TX, United States * Corresponding author; email: lstaudt{at}mail.nih.gov. A gene expression signature of tumor proliferation rate in mantle cell lymphoma (MCL) is an overriding molecular predictor of the length of survival following diagnosis. Many strongly proliferative MCL tumors have exceptionally high Cyclin D1 mRNA levels and preferentially express short Cyclin D1 mRNA isoforms. We demonstrate here that these short mRNAs are Cyclin D1a isoforms with truncated 3'UTRs, not alternatively spliced Cyclin D1b mRNA isoforms. Among 15 MCL tumors with truncated Cyclin D1 mRNAs, 7 had genomic deletions in the Cyclin D1 3'UTR region. In 3 others, the Cyclin D1 gene contained point mutations that created premature polyadenylation signals, giving rise to 1.5 kb mRNAs lacking most of the 3'UTR. Both types of genomic alteration created transcripts lacking mRNA destabilization elements present in the wild-type Cyclin D1a mRNA. Premature polyadenylation due to a 3'UTR mutation was also present in the Z-138 MCL cell line, which expressed both truncated and full length Cyclin D1a mRNAs. In these cells, the half-life of the short Cyclin D1a mRNA was much longer than that of the full length mRNA. We conclude that alterations of Cyclin D1 3’UTR structure can significantly increase its oncogenic effect and worsen the clinical course of MCL patients. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Bea, I. Salaverria, L. Armengol, M. Pinyol, V. Fernandez, E. M. Hartmann, P. Jares, V. Amador, L. Hernandez, A. Navarro, et al. Uniparental disomies, homozygous deletions, amplifications, and target genes in mantle cell lymphoma revealed by integrative high-resolution whole-genome profiling Blood, March 26, 2009; 113(13): 3059 - 3069. [Abstract] [Full Text] [PDF] S. J. Freemantle, Y. Guo, and E. Dmitrovsky Retinoid Chemoprevention Trials: Cyclin D1 in the Crosshairs Cancer Prevention Research, January 1, 2009; 2(1): 3 - 6. [Full Text] [PDF] V. K. Gupta, A. Feber, L. Xi, A. Pennathur, M. Wu, J. D. Luketich, and T. E. Godfrey Association between CCND1 G/A870 Polymorphism, Allele-Specific Amplification, Cyclin D1 Expression, and Survival in Esophageal and Lung Carcinoma Clin. Cancer Res., December 1, 2008; 14(23): 7804 - 7812. [Abstract] [Full Text] [PDF] E. Hartmann, V. Fernandez, V. Moreno, J. Valls, L. Hernandez, F. Bosch, P. Abrisqueta, W. Klapper, M. Dreyling, E. Hoster, et al. Five-Gene Model to Predict Survival in Mantle-Cell Lymphoma Using Frozen or Formalin-Fixed, Paraffin-Embedded Tissue J. Clin. Oncol., October 20, 2008; 26(30): 4966 - 4972. [Abstract] [Full Text] [PDF] R Shakir, N Ngo, and K N Naresh Correlation of cyclin D1 transcript levels, transcript type and protein expression with proliferation and histology among mantle cell lymphoma J. Clin. Pathol., August 1, 2008; 61(8): 920 - 927. [Abstract] [Full Text] [PDF] R. W. Chen, L. T. Bemis, C. M. Amato, H. Myint, H. Tran, D. K. Birks, S. G. Eckhardt, and W. A. Robinson Truncation in CCND1 mRNA alters miR-16-1 regulation in mantle cell lymphoma Blood, August 1, 2008; 112(3): 822 - 829. [Abstract] [Full Text] [PDF] C. A. Tucker, A. I. Kapanen, G. Chikh, B. G. Hoffman, A. H. Kyle, I. M. Wilson, D. Masin, R. D. Gascoyne, M. Bally, and R. J. Klasa Silencing Bcl-2 in models of mantle cell lymphoma is associated with decreases in cyclin D1, nuclear factor-{kappa}B, p53, bax, and p27 levels Mol. Cancer Ther., April 1, 2008; 7(4): 749 - 758. [Abstract] [Full Text] [PDF] O. A. O'Connor Mantle Cell Lymphoma: Identifying Novel Molecular Targets in Growth and Survival Pathways Hematology, January 1, 2007; 2007(1): 270 - 276. [Abstract] [Full Text] [PDF]

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