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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-01-0263.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3181-3187
NEOPLASIA
Sequestration of p27Kip1 protein by cyclin D1 in
typical and blastic variants of mantle cell lymphoma (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
From the Hematopathology Section, Laboratory of
Pathology, National Cancer Institute, National Institutes of Health,
Bethesda, MD; Institute of Pathology, GSF-National Research Center for
Environment and Health, Neuherberg, Germany; Institute of
Pathology, Technical University, Munich, Germany; and the
Hospital Clinic Provincial, University of Barcelona, Barcelona,
Spain.
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 in MCL, as assessed by immunohistochemistry (IHC), does not
show the usual inverse relationship to proliferate seen in most other
lymphomas that do not overexpress cyclin D1. This suggested that the
normal expression 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 MCLs showed lower expression of p27
when compared to the more highly proliferative blastic cases or cell
lines (mean arbitrary units: 58 versus 236 versus 120). Cyclin D1 was
expressed at variable levels in both typical and blastic MCLs. 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 complexes containing cyclin D1. 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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