are highly sensitive to selective inhibition of CDK 4 kinase activity Mantle cell lymphoma cells express predominantly Cyclin D 1 a isoform

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. Introduction only. For personal use at PENN STATE UNIVERSITY on February 22, 2013. bloodjournal.hematologylibrary.org From