Deletion of RDINK4/ARF enhancer: A novel mutation to “inactivate” the INK4-ARF locus

The presence of an enhancer element, RDINK4/ARF (RD), in the prominent INK4-ARF locus provides a novel en bloc mechanism to simultaneously regulate the transcription of the p15INK4B (p15), p16INK4A (p16), and p14ARF tumor suppressor genes. While genetic inactivation of p15, p16, and p14ARF in human cancers has been extensively studied, little is known about RD alteration and its potential contributions to cancer progression. In this review, we discuss recent developments in RD alteration and its association with p15, p16, and p14ARF alterations in human cancers, and demonstrate that RD deletion may represent a novel mechanism to simultaneously down-regulate p15, p16, and p14ARF, thus promoting carcinogenesis.