January 2001, Volume 15, Issue 1, Pages 157 - 165

Original Manuscript

Hypermethylation of p16INK4A gene promoter during the progression of plasma cell dyscrasia T Uchida1,2, T Kinoshita1, T Ohno1, H Ohashi1, H Nagai1 & H Saito1 1First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan     2Department of Hematology, Nagoya Daini Red Cross Hospital, Nagoya, Japan     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

Keywords

p16INK4A;   p15INK4B;   promoter hypermethylation;   disease progression;   plasma cell dyscrasia;   tumor suppressor gene

Abstract

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 p16INK4A and p15INK4B 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 p16INK4Aand p15INK4B 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 p16INK4A gene (15/37, 41%), whereas p15INK4B gene methylation was not so frequent (5/37, 14%). Many patients whose BM-MNC showed dense methylation of the p16INK4A gene had extramedullary plasmacytoma (extra-PC), and all available extra-PC samples showed alterations of the p16INK4A gene (4; dense methylation, 1; homozygous deletion). In contrast to MM, hypermethylation of the p16INK4A 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 p16INK4A gene promoter contributes to progression to aggressive MM from indolent PCD, especially to extra-PC development. Leukemia (2001) 15, 157-165.

Received 25 April 2000; Accepted 7 September 2000

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