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

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

^* To whom correspondence should be addressed. E-mail: phinds{at}tuftsmedicalcenter.org.

	Abstract

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]

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