Abstract
Bone morphogenetic proteins (BMP), belonging to the transforming growth factorβΞ² superfamily, are multifunctional regulators of cell proliferation, differentiation and apoptosis in various types of malignant cells. In this study, we investigated BMPβ6 promoter methylation in patients with various types of leukemias. The BMPβ6 methylation was found preferentially in adult Tβcell leukemia (ATL) (49 of 60, 82%) compared with other types of leukemias studied including acute myeloid leukemia (3 of 67, 5%), acute lymphoblastic leukemia (6 of 38, 16%) and chronic lymphocytic leukemia (1 of 21, 5%). Among subtypes of ATL, the BMPβ6 gene was more frequently methylated in aggressive ATL forms of acute (96%) and lymphoma (94%) types than less malignant chronic ATL (44%) and smoldering ATL (20%). We also analyzed the methylation status of peripheral blood mononuclear cells from healthy donors and nonmalignant lymph nodes with reactive lymphadenopathy, none of which showed detectable BMPβ6 methylation in this study. The BMPβ6 methyaltion was correlated with decreased mRNA transcript and protein expression. Expression of BMPβ6 was restored by the demethylating agent 5βazaβ2β²βdeoxycytidine, suggesting that methylation was associated with the transcriptional silencing. Serial analysis demonstrated an increasing methylation of CpG sites in the BMPβ6 promoter and the resultant suppression of BMPβ6 expression as ATL progressed. These findings suggested that BMPβ6 promoter methylation is likely to be a common epigenetic event at later stages of ATL and that the methylation profiles may be useful for the staging of ATL as well as for evaluation of the individual risk of developing the disease. Β© 2008 WileyβLiss, Inc.