HYPERMETHYLATION OF THE P15(INK4B) GENE IN MYELODYSPLASTIC SYNDROMES

Previous studies have shown that the cyclin-dependent kinase inhibitor (CDKI) genes p15(INK4B) and p16(INK4A) are frequently inactivated by genetic alterations in many malignant tumors and that they are candida te tumor-suppressor genes, Although genetic alterations in these genes may be limited to lymphoid malignancies, it has been reported that th eir inactivation by aberrant methylation of 5' CpG islands may be invo lved in various hematologic malignancies. In this study, we investigat ed the p15(INK4B) and p16(INK4A) genes to clarify their roles in the p athogenesis of myelodysplastic syndrome (MDS). Southern blotting analy sis showed no gross genetic alterations in either of these genes, Howe ver, hypermethylation of the 5' CpG island of the p15(INK4B) gene occu rred frequently in patients with MDS (16/32 [50%]). Interestingly, the p15(INK4B) gene was frequently methylated in patients with high-risk MDS (refractory anemia with excess blasts [RAEB], RAEB in transformati on [RAEB-t], and overt leukemia evolved from MDS; 14/18 [78%]) compare d with patients with low-risk MDS (refractory anemia [RA] and refracto ry anemia with ring sideroblast [RARS]; 1/12 [8%]). Furthermore, methy lation status of the p15(INK4B) gene was progressed with the developme nt of MDS in most patients examined, In contrast, none of the MDS pati ents showed apparent hypermethylation of the p16(INK4A) gene. These re sults suggest that hypermethylation of the p(15INK4B) gene is involved in the pathogenesis of MDS and is one of the important late events du ring the development of MDS. (C) 1997 by The American Society of Hemat ology.