Submitted April 11, 2006
Accepted April 27, 2006
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*
University of Pennsylvania Medical Center, Dept. of Pathology and Laboratory Medicine, Philadelphia
University of Alberta and Cross Center Institute, Alberta, Canada
University of Pennsylvania Medical Center, Dept. of Cancer Biology, Philadelphia, PA, USA
Pfizer Global Research and Development, Ann Arbor, MI and San Diego, CA, USA
University of Pennsylvania Medical Center, Dept. of Medicine, Philadelphia, PA, USA
University of Pennsylvania Medical Cntr, Dept. of Cancer Biology and Abramson Family Cancer Res Inst
* Corresponding author; email: wasik{at}mail.med.upenn.edu.
Mantle cell lymphoma (MCL) has a rather poor prognosis
and currently 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 whereas three out of four MCL
cell lines expressed the recently identified, highly
oncogenic Cyclin D1b isoform, in addition to the
canonical Cyclin D1a , eight MCL patient samples
expressed only the Cyclin D1a protein despite expressing
detectable Cyclin D1b mRNA. Both 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 co-
association. All MCL cell lines and tissues examined
displayed non-detectable to diminished expression of the
Cyclin D1 inhibitor p16. Novel small molecule CDK4/6
inhibitor PD0332991 profoundly suppressed at low nM
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.
