Hypermethylation of the p15(INK4B) gene in myelodysplastic syndromes

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Abstract

Previous studies have shown that the cyclin-dapendent kinase inhibitor (CDKI) genes p15(INK4B) and p16(INK4A) are frequently inactivated by genetic alterations in many malignant tumors and that they are candidate tumor- suppressor genes. Although genetic alterations in these genes may be limited to lymphoid malignancies, it has been reported that their inactivation by aberrant methylation of 5' CpG islands may be involved in various hematologic malignancies. In this study, we investigated the p15(INK4B) and p16(INK4A) genes to clarify their roles in the pathogenesis of myelodysplastic syndrome (MDS). Southern blotting analysis showed no gross genetic alterations in either of these genes. However, hypermethylation of the 5' CpG island of the p15(INK4B) gene occurred 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 transformation [RAEB-t], and overt leukemia evolved from MDS; 14/18 [78%]) compared with patients with low-risk MDS (refractory anemia [RA] and refractory anemia with ring sideroblast [RARS]; 1/12 [8%]). Furthermore, methylation status of the p15(INK4B) gene was progressed with the development of MDS in most patients examined. In contrast, none of the MDS patients showed apparent hypermethylation of the p16(INK4A)gene. These results suggest that hypermethylation of the p15(INK4B) gene is involved in the pathogenesis of MDS and is one of the important late events during the development of MDS.

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Uchida, T., Kinoshita, T., Nagai, H., Nakahara, Y., Saito, H., Hotta, T., & Murate, T. (1997). Hypermethylation of the p15(INK4B) gene in myelodysplastic syndromes. Blood, 90(4), 1403–1409. https://doi.org/10.1182/blood.v90.4.1403

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