Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia.

Abstract

D-type cyclins form complexes with cyclin-dependent kinases (CDK4/6) and promote cell cycle progression. Although cyclin D functions appear largely tissue specific, we demonstrate that cyclin D3 has unique functions in lymphocyte development and cannot be replaced by cyclin D2, which is also expressed during blood differentiation. We show that only combined deletion of p27(Kip1) and retinoblastoma tumor suppressor (Rb) is sufficient to rescue the development of Ccnd3(-/-) thymocytes. Furthermore, we show that a small molecule targeting the kinase function of cyclin D3:CDK4/6 inhibits both cell cycle entry in human T cell acute lymphoblastic leukemia (T-ALL) and disease progression in animal models of T-ALL. These studies identify unique functions for cyclin D3:CDK4/6 complexes and suggest potential therapeutic protocols for this devastating blood tumor.

• Authors: Catherine M Sawai, Jacquelyn Freund, Philmo Oh, Delphine Ndiaye-Lobry, Jamieson C Bretz, Alexandros Strikoudis, Lali Genesca, Thomas Trimarchi, Michelle A Kelliher, Marcus Clark, Jean Soulier, Selina Chen-Kiang, Iannis Aifantis
• Journal: Cancer cell (Cancer Cell) Vol. 22 Issue 4 Pg. 452-65 (Oct 16 2012) ISSN: 1878-3686 [Electronic] United States
• PMID: 23079656 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Cyclin D2
• Cyclin D3
• Receptor, Notch1
• Retinoblastoma Protein
• Cyclin-Dependent Kinase Inhibitor p27
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Animals
• Cyclin D2 (physiology)
• Cyclin D3 (antagonists & inhibitors, physiology)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors, physiology)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors, physiology)
• Cyclin-Dependent Kinase Inhibitor p27 (physiology)
• Humans
• Lymphocytes (physiology)
• Mice
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, etiology)
• Receptor, Notch1 (physiology)
• Retinoblastoma Protein (physiology)