CDK4 and central nervous system cancer: Thus, nearly all WHO grade III and IV (GBM) show a disruption of cell cycle due to alterations in one out of three genetic loci governing G1 arrest such as: CDK4, INK4a–ARF or Rb. Over half of high-grade human gliomas lack a functional INK4a–ARF locus [9], [10] and hence can produce neither p16INK4a nor p19ARF, the two proteins encoded by this locus [11].