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

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.

Pubmed ID: 23079656

Authors

  • Sawai CM
  • Freund J
  • Oh P
  • Ndiaye-Lobry D
  • Bretz JC
  • Strikoudis A
  • Genesca L
  • Trimarchi T
  • Kelliher MA
  • Clark M
  • Soulier J
  • Chen-Kiang S
  • Aifantis I

Journal

Cancer cell

Publication Data

October 16, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: 5 P30CA16087-31
  • Agency: NCI NIH HHS, Id: 5P30CA16087-31
  • Agency: NCI NIH HHS, Id: P30 CA016087-30
  • Agency: NCI NIH HHS, Id: R01 CA096899
  • Agency: NCI NIH HHS, Id: R01 CA105129
  • Agency: NCI NIH HHS, Id: R01 CA133379
  • Agency: NCI NIH HHS, Id: R01 CA149655
  • Agency: NIGMS NIH HHS, Id: R01 GM088847
  • Agency: NCI NIH HHS, Id: R01CA105129
  • Agency: NCI NIH HHS, Id: R01CA133379
  • Agency: NCI NIH HHS, Id: R01CA149655
  • Agency: NIGMS NIH HHS, Id: R01GM088847
  • Agency: NCI NIH HHS, Id: R21CA141399
  • Agency: NIGMS NIH HHS, Id: T32 GM007308
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Cyclin D2
  • Cyclin D3
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinase Inhibitor p27
  • Humans
  • Lymphocytes
  • Mice
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Receptor, Notch1
  • Retinoblastoma Protein