1. ¹Institute of Pathology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany
2. ²Institute of Stem Cell Research, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany
3. ³Institute of Toxicology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany
4. ⁴Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
5. ⁵Institute of Pathology, Eberhard-Karls-University, Tuebingen, Germany

Correspondence: Dr L Quintanilla-Martinez, Institute of Pathology, Helmholtz Center Munich-German Research Center for Environmental Health, Building 35, Room 2055, Ingolstädter Landstrae 1, 85764 Neuherberg, Germany. E-mail: quintanilla-fend@helmholtz-muenchen.de

Received 24 January 2008; Revised 2 June 2008; Accepted 7 July 2008; Published online 7 August 2008.

Abstract

Cyclin D1 overexpression is the hallmark of mantle cell lymphoma (MCL). However, the importance of cyclin D1 in the maintenance and progression of the disease remains to be defined. The aim of this study was to elucidate the role of cyclin D1 overexpression using an efficient cyclin D1-shRNA and a lentiviral system in well-characterized MCL cell lines. Surprisingly, the knockdown of cyclin D1 led to a moderate retardation in growth, without induction of apoptosis. The cyclin D1-shRNA-transduced MCL cells showed a 15% shift from S phase to G₁ phase of the cell cycle, a weak induction of p27^Kip1, decreased Rb (Ser807/811) phosphorylation, and a consistent upregulation of cyclin D2 mRNA and protein expression. However, double knockdown of cyclins D1 and D2 did not intensify the effects observed with cyclin D1 knockdown alone. These data suggest that the moderate effects of cyclin D1 downregulation on survival and proliferation are likely the result of compensatory cyclin-independent mechanisms governing proliferation or alternatively, secondary genetic events that make cyclin D1 dispensable. These findings have important implications for MCL therapy, as strategies targeting only cyclin D1 function might be hampered by compensatory regulatory mechanisms, resulting in a low probability of treatment response.