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A Requirement for Cyclin-Dependent Kinase 6 in Thymocyte Development and Tumorigenesis

¹ Molecular Oncology Research Institute, Tufts Medical Center; ² Department of Pathology and ³ Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ⁴ Dental Research Institute, University of California-Los Angeles, Los Angeles, California; ⁵ Department of Biology, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; and ⁶ Department of Medicine, Committee on Immunology, University of Chicago, Chicago, Illinois

Requests for reprints: Philip W. Hinds or Miaofen G. Hu, Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street #5609, Boston, MA 02111. Phone: 617-636-7947; Fax: 617-636-7813; E-mail: phinds{at}tuftsmedicalcenter.org or mhu{at}tuftsmedicalcenter.org.

Key Words: CDK6 • thymocytes • thymus • development • tumorigenesis

Cyclin-dependent kinase 6 (CDK6) promotes cell cycle progression and is overexpressed in human lymphoid malignancies. To determine the role of CDK6 in development and tumorigenesis, we generated and analyzed knockout mice. Cdk6-deficient mice show pronounced thymic atrophy due to reduced proliferative fractions and concomitant transitional blocks in the double-negative stages. Using the OP9-DL1 system to deliver temporally controlled Notch receptor–dependent signaling, we show that CDK6 is required for Notch-dependent survival, proliferation, and differentiation. Furthermore, CDK6-deficient mice were resistant to lymphomagenesis induced by active Akt, a downstream target of Notch signaling. These results show a critical requirement for CDK6 in Notch/Akt-dependent T-cell development and tumorigenesis and strongly support CDK6 as a specific therapeutic target in human lymphoid malignancies. [Cancer Res 2009;69(3):810–8]