Author/Authors :
Sawai، نويسنده , , Catherine M. and Freund، نويسنده , , Jacquelyn and Oh، نويسنده , , Philmo and Ndiaye-Lobry، نويسنده , , Delphine and Bretz، نويسنده , , Jamieson C. and Strikoudis، نويسنده , , Alexandros and Genesca، نويسنده , , Lali and Trimarchi، نويسنده , , Thomas and Kelliher، نويسنده , , Michelle A. and Clark، نويسنده , , Marcus and Soulier، نويسنده , , Jean and Chen-Kiang، نويسنده , , Selina and Aifantis، نويسنده , , Iannis، نويسنده ,
Abstract :
Summary
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 p27Kip1 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.
