A requirement for cyclin-dependent kinase 6 in thymocyte development and 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.
Hu
Miaofen G
MG
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA. mhu@tuftsmedicalcenter.org
Deshpande
Amit
A
Enos
Miriam
M
Mao
Daqin
D
Hinds
Elisabeth A
EA
Hu
Guo-fu
GF
Chang
Rui
R
Guo
Zhuyan
Z
Dose
Marei
M
Mao
Changchuin
C
Tsichlis
Philip N
PN
Gounari
Fotini
F
Hinds
Philip W
PW
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008223:Lymphoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt; D051880:Receptors, Notch; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D013953:Thymus Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
D051880:Receptors, Notch; D051058:Oncogene Protein v-akt; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6