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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-01-0263.
Submitted January 29, 2002
Accepted December 3, 2002
Sequestration of p27Kip1 protein by cyclin D1 in typical and blastic variants of mantle cell lymphomas (MCL): implications for pathogenesis
Leticia Quintanilla-Martinez, Theresa Davies-Hill, Falko Fend, Julia Calzada-Wack, Lynn Sorbara, Elias Campo, Elaine S Jaffe, and Mark Raffeld*
Institute of Pathology, GSF-Research Center, Oberschleissheim, Germany
Laboratory of Pathology, Hematopathology Section, National Institutes of Health (NIH), National Cancer Institue, Bethesda, MD, USA
Institute of Pathology, Technical University Munich, Munich, Germany
Department of Pathology, Hospital Clinic Provincial, University of Barcelona, Barcelona, Spain
* Corresponding author; email: mraff{at}box-m.nih.gov.
P27 is a cyclin-dependent kinase inhibitor that plays a critical role in regulating G1/S progression, and whose activity is, in part, regulated through interactions with D type cyclins. Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation resulting in deregulated cyclin D1. We previously showed that p27 expression, as assessed by immunohistochemistry (IHC) in MCL, does not show the usual inverse relationship to proliferation seen in most other lymphomas that do not overexpress cyclin D1. This suggested that the normal expression and/or control of p27 activity on cell growth might be altered through potential interactions with cyclin D1. Using Western blot and coimmunoprecipitation studies, we assessed the interrelationship between cyclin D1 and p27 in several cyclin D1+ cell lines and primary MCL cases. Similar to our previous results by IHC, typical MCL showed lower expression of p27 when compared to the more highly proliferative blastic cases or cell lines (mean arbitrary units: 58 Vs 236 Vs 120). Cyclin D1 was expressed at variable levels in both typical and blastic MCL. P27 protein could be consistently coimmunoprecipitated with cyclin D1 from both cell lines and cases. Using techniques of exhaustive immunoprecipitation, we could demonstrate that most p27 protein was sequestered into cyclin D1 containing complexes. We hypothesize that mantle cell lymphomagenesis results not only from direct consequences of inappropriate cyclin D1 expression, but also from the ability of overexpressed cyclin D1 to buffer physiologic changes in p27 levels, thereby rendering p27 ineffective as an inhibitor of cellular growth.
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