Hypermethylation-associated Inactivation Indicates a Tumor Suppressor Role for p15^INK4B

Abstract

The recently identified cyclin-dependent kinase inhibitor p15^INK4B is localized to a region on chromosome 9p21 frequently deleted in human tumors. Previous evidence has pointed to a related gene, p16^INK4A, as the principal target of this deletion. We report that in gliomas and, to a striking degree, in leukemias, the p15 gene is commonly inactivated in association with promoter region hypermethylation involving multiple sites in a 5′-CpG island. In some gliomas and all of the primary leukemias, this event occurs without alteration of the adjacent gene, p16^INK4A. In other tumors, including lung, head and neck, breast, prostate, and colon cancer, inactivation of p16^INK4B occurs only rarely and only with concomitant inactivation of p16. Aberrant methylation of p15^INK4B is associated with transcriptional loss of this gene. Treatment with the demethylating agent 5-aza-2′-deoxycytidine leads to re-expression of p15 mRNA. In selected leukemia cell lines, p15 inactivation correlates with known resistance to the growth-suppressive effects of transforming growth factor-β. These results suggest that p15^INK4B is inactivated selectively in leukemias and gliomas and seems to constitute an important tumor suppressor gene loss in these neoplasms.