Promoter methylation of the bone morphogenetic protein‐6 gene in association with adult T‐cell leukemia
Open Access
- 13 August 2008
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 123 (8), 1824-1831
- https://doi.org/10.1002/ijc.23749
Abstract
Bone morphogenetic proteins (BMP), belonging to the transforming growth factor‐β superfamily, are multifunctional regulators of cell proliferation, differentiation and apoptosis in various types of malignant cells. In this study, we investigated BMP‐6 promoter methylation in patients with various types of leukemias. The BMP‐6 methylation was found preferentially in adult T‐cell 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 BMP‐6 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 BMP‐6 methylation in this study. The BMP‐6 methyaltion was correlated with decreased mRNA transcript and protein expression. Expression of BMP‐6 was restored by the demethylating agent 5‐aza‐2′‐deoxycytidine, suggesting that methylation was associated with the transcriptional silencing. Serial analysis demonstrated an increasing methylation of CpG sites in the BMP‐6 promoter and the resultant suppression of BMP‐6 expression as ATL progressed. These findings suggested that BMP‐6 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.This publication has 46 references indexed in Scilit:
- TGF-β and cancerCytokine & Growth Factor Reviews, 2006
- Identification of Aberrantly Methylated Genes in Association with Adult T-Cell LeukemiaCancer Research, 2004
- Cytostatic and apoptotic actions of TGF-β in homeostasis and cancerNature Reviews Cancer, 2003
- TGF-β signaling in tumor suppression and cancer progressionNature Genetics, 2001
- Multiple Viral Strategies of HTLV-1 for Dysregulation of Cell Growth ControlAnnual Review of Immunology, 2001
- TGFβ Signaling in Growth Control, Cancer, and Heritable DisordersCell, 2000
- TGF-β SIGNAL TRANSDUCTIONAnnual Review of Biochemistry, 1998
- The CDKN2 gene alterations in various types of adult T‐cell leukaemiaBritish Journal of Haematology, 1996
- Diagnostic criteria and classification of clinical subtypes of adult T‐cell leukaemia‐lymphomaBritish Journal of Haematology, 1991
- Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease.Proceedings of the National Academy of Sciences of the United States of America, 1982