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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1744-1750. Prepublished online as a Blood First Edition Paper on May 11, 2006; DOI 10.1182/blood-2006-04-016634. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-04-016634v1 108/5/1744    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 Marzec, M. Articles by Wasik, M. A. Search for Related Content PubMed PubMed Citation Articles by Marzec, M. Articles by Wasik, M. A. Related Collections Neoplasia Cell Cycle Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity Michal Marzec, Monika Kasprzycka, Raymond Lai, Andrew B. Gladden, Pawel Wlodarski, Ewa Tomczak, Peter Nowell, Samuel E. DePrimo, Seth Sadis, Stephen Eck, Stephen J. Schuster, J. Alan Diehl, and Mariusz A. Wasik From the Departments of Pathology and Laboratory Medicine, Cancer Biology, and Medicine, and the Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia; the University of Alberta and Cross Cancer Institute, Edmonton, AB, Canada; and Pfizer Global Research and Development, Ann Arbor, MI, and San Diego, CA. The prognosis for patients with mantle cell lymphoma (MCL) is poor, and at present there is no truly effective therapy. Gene translocation-mediated constitutive expression of cyclin D1 seems to play the key role in the pathogenesis of MCL. Here we report that although 3 of 4 MCL cell lines expressed the recently identified, highly oncogenic cyclin D1b isoform, as well as the canonical cyclin D1a, 8 MCL patient samples expressed only the cyclin D1a protein despite expressing detectable cyclin D1b mRNA. Cell lines and tissue samples displayed constitutive activation of the cyclin D1 signaling cascade, as evidenced by strong expression of CDK4, Rb phosphorylation, and cyclin D1/CDK4 coassociation. All MCL cell lines and tissues examined displayed nondetectable to diminished expression of the cyclin D1 inhibitor p16. Novel small molecule CDK4/CDK6 inhibitor PD0332991 profoundly suppressed—at low nanomolar concentrations—Rb phosphorylation, proliferation, and cell cycle progression at the G0/G1 phase of MCL cells. These findings provide evidence that MCL should be very sensitive to targeted therapy aimed at functional inhibition of the cyclin D1/CDK4 complex. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Menu, J. Garcia, X. Huang, M. Di Liberto, P. L. Toogood, I. Chen, K. Vanderkerken, and S. Chen-Kiang A Novel Therapeutic Combination Using PD 0332991 and Bortezomib: Study in the 5T33MM Myeloma Model Cancer Res., July 15, 2008; 68(14): 5519 - 5523. [Abstract] [Full Text] [PDF] G. Sanchez, D. Bittencourt, K. Laud, J. Barbier, O. Delattre, D. Auboeuf, and M. Dutertre Alteration of cyclin D1 transcript elongation by a mutated transcription factor up-regulates the oncogenic D1b splice isoform in cancer PNAS, April 22, 2008; 105(16): 6004 - 6009. [Abstract] [Full Text] [PDF] L. Wang, J. Wang, B. W. Blaser, A.-M. Duchemin, D. F. Kusewitt, T. Liu, M. A. Caligiuri, and R. Briesewitz Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia Blood, September 15, 2007; 110(6): 2075 - 2083. [Abstract] [Full Text] [PDF]

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