Abstract

Keywords

Hypermethylation of p16^INK4A gene promoter during the progression of plasma cell dyscrasia

T Uchida^1,2, T Kinoshita¹, T Ohno¹, H Ohashi¹, H Nagai¹ & H Saito¹

Correspondence to: T Uchida, Department of Hematology, Nagoya Daini Red Cross Hospital, 2-9, Myoken-cho, Showa-ku, Nagoya 466-8650, Japan; Fax: +81-52-832-1130

Recent studies have indicated a close relationship between inactivation of tumor suppressor genes (TSGs) and disease progression. The genes encoding the cyclin-dependent kinase inhibitors p16^INK4A and p15^INK4B are potent TSGs, and correlations between their inactivation and disease progression have also been reported in various malignancies. In this study, we analyzed the methylation status of p16^INK4Aand p15^INK4B gene promoters in plasma cell dyscrasias (PCDs) by methylation-specific PCR (MSP). In analyses using DNAs extracted from bone marrow mononuclear cells (BM-MNCs), patients with multiple myeloma (MM) showed frequent hypermethylation of the p16^INK4A gene (15/37, 41%), whereas p15^INK4B gene methylation was not so frequent (5/37, 14%). Many patients whose BM-MNC showed dense methylation of the p16^INK4A gene had extramedullary plasmacytoma (extra-PC), and all available extra-PC samples showed alterations of the p16^INK4A gene (4; dense methylation, 1; homozygous deletion). In contrast to MM, hypermethylation of the p16^INK4A gene was significantly infrequent in indolent PCDs (2/22, 9%, P = 0.0055). The infrequency in indolent PCDs was also confirmed by analyses using DNAs extracted from BM smears (1/29, 3%). It is possible that hypermethylation of the p16^INK4A gene promoter contributes to progression to aggressive MM from indolent PCD, especially to extra-PC development. Leukemia (2001) 15, 157–165.

^© Macmillan Publishers Ltd 2001