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

Cancer Cell. 2012 Oct 16;22(4):452-65. doi: 10.1016/j.ccr.2012.09.016.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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

Associated data

  • GEO/GSE40635