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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 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 Citation Map 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. Related Collections Neoplasia Gene Expression Free Research Articles Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLENARY PAPER Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival Adrian Wiestner1,2, Mahsa Tehrani2, Michael Chiorazzi1, George Wright1, Federica Gibellini2, Kazutaka Nakayama2, Hui Liu2, Andreas Rosenwald3, H. Konrad Muller-Hermelink3, German Ott3, Wing C. Chan4, Timothy C. Greiner4, Dennis D. Weisenburger4, Julie Vose4, James O. Armitage4, Randy D. Gascoyne5, Joseph M. Connors5, Elias Campo6, Emilio Montserrat6, Francesc Bosch6, Erlend B. Smeland7, Stein Kvaloy7, Harald Holte7, Jan Delabie7, Richard I. Fisher8, Thomas M. Grogan8, Thomas P. Miller8, Wyndham H. Wilson1, Elaine S. Jaffe1, Louis M. Staudt, for the Lymphoma/Leukemia Molecular Profiling Project1 1 Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD; 2 Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD; 3 University of Würzburg, Germany; 4 University of Nebraska Medical Center, Omaha, NE; 5 British Columbia Cancer Center, Vancouver, BC, Canada; 6 Hospital Clinic, University of Barcelona, Spain; 7 Norwegian Radium Hospital, Oslo, Norway; 8 Southwest Oncology Group, San Antonio, TX 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 CCND1 3'UTR region. In 3 others, CCND1 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 also was 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 CCND1 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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