Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity.
The prognosis for patients with mantle cell lymphoma (MCL) is poor, and at present there is 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 although 3 of 4 MCL cell lines expressed the recently identified, highly oncogenic cyclin D1b isoform, as well as the canonical cyclin D1a, 8 MCL patient samples expressed only the cyclin D1a protein despite expressing detectable cyclin D1b mRNA. 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 coassociation. All MCL cell lines and tissues examined displayed nondetectable to diminished expression of the cyclin D1 inhibitor p16. Novel small molecule CDK4/CDK6 inhibitor PD0332991 profoundly suppressed--at low nanomolar 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.
Marzec
Michal
M
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania Medical Center, 7.106 Founders, Philadelphia, PA 19104, USA.
Kasprzycka
Monika
M
Lai
Raymond
R
Gladden
Andrew B
AB
Wlodarski
Pawel
P
Tomczak
Ewa
E
Nowell
Peter
P
Deprimo
Samuel E
SE
Sadis
Seth
S
Eck
Stephen
S
Schuster
Stephen J
SJ
Diehl
J Alan
JA
Wasik
Mariusz A
MA
D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D019940:Genes, bcl-1; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000469:parasitology; D010879:Piperazines / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction
D010879:Piperazines; D020033:Protein Isoforms; D011725:Pyridines; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; C500026:palbociclib