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  • Commentary and Mini Review
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Commentary and Mini-Review

Gene silencing of the p15/INK4B cell-cycle inhibitor by hypermethylation: an early or later epigenetic alteration in myelodysplastic syndromes?

Leukemia volume 17, pages 1762–1764 (2003)Cite this article

In their paper published in this issue of Leukemia, Aoki and et al1 have addressed important questions regarding the mechanisms mediating a regional, inactiving promoter methylation of the p15/INK4B gene in myelodysplastic syndromes (MDS). Based on a recent report of coordinate overexpression of DNA methyltransferase (DNMT) -1, -3a and -3b, and a correlation between p15 methylation and DNMT overexpression in acute myeloid leukemia (AML; Mizuno et al2), they asked whether this correlation is also present in MDS. They demonstrate overexpression of DNMT1 and DNMT3b in several control leukemia cell lines, even after equalizing mRNA levels to a cell-cycle-dependent gene (histone H4, necessary to compensate for the known DNMT expression changes during cell cycle). However, no significant increase in DNMT expression was apparent in mononuclear cells from MDS patients compared to those from individuals with normal bone marrow. Furthermore, mRNA expression levels of the three DNMTs did not significantly differ between MDS cases with vs without p15 promoter methylation.

In the majority of solid tumors and hematologic neoplasias, hypermethylation of numerous genes, which are otherwise both unmethylated and expressed in a regulated manner in the normal cellular counterparts, can be detected.3,4 These include p16 and p15, p14/ARF, p21/WAF, p73, BRCA1, MTMG6, GSTP-1, RASSF1A, VHL, E-cadherin, estrogen receptor, androgen receptor, and calcitonin. Thus, genes encoding proteins involved in control of cell proliferation and differentiation, detoxification, DNA repair, signalling, adhesion, and metastasis can be inactivated by this epigenetic mechanism in cancer. Some of the targets of cancer-associated methylation are putative or bona fide tumor suppressor genes. Thus, epigenetic inactivation is considered an oncogenic event similar to genetic alterations of tumor suppressors, such as mutations or deletions. Hypermethyl-ation patterns in malignancy may be quite tissue-specific: for instance, p16 is frequently methylated in epithelial neoplasias, non-Hodgkin‘s lymphoma, and multiple myeloma, but only rarely in myeloid neoplasias, in which, however, the closely related p15 is frequently silenced.5 Both p15 and p16 are inhibitors of cyclin-dependent kinases (CDK) 4 and 6, thus controlling G1/S transition in the cell cycle, with p15 being a downstream target of TGF-β under physiologic conditions. While their functions are of some redundance as to CDK inhibition, p15 inactivation by methylation or deletion appears to be specific both in a mouse model of radiation-induced hematopoietic malignancy6 and in primary myeloid neoplasia. The phenotype of knockout mice with homozygous deletion of the p15 gene is associated with lymphoproliferative neoplasias, tumors, and cysts.7

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Acknowledgements

Support by Wilhelm-Sander-Stiftung, Deutsche Forschungsgemeinschaft and José Carreras Stiftung is acknowledged.

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  1. Department Internal Medicine I, Division of Hematology/Oncology, University of Freiburg Medical Center, Freiburg, Germany

    M Lübbert

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Lübbert, M. Gene silencing of the p15/INK4B cell-cycle inhibitor by hypermethylation: an early or later epigenetic alteration in myelodysplastic syndromes?. Leukemia 17, 1762–1764 (2003). https://doi.org/10.1038/sj.leu.2403045

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