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Relationship between methylation of the p15 gene in myelodysplastic syndromes (MDS)

Leukemia volume 15, pages 990–991 (2001)Cite this article

Transcription of the p15(INK4B) tumor suppressor gene, which encodes a cyclin-dependent kinase inhibitor, is positively regulated by transforming growth factor-β (TGF-β). We previously reported that the hypermethylation of the p15 gene promoter, which should silence gene expression, was frequently observed in myelodysplastic syndromes (MDS), and it may be associated with disease progression.1 Another molecular abnormality frequently found in MDS is the ectopic expression of the ecotropic virus integration site-1 (EVI-1) gene. The EVI-1 gene was cloned as a gene activated by viral integration in murine leukemia cells, and the human gene was located on the long arm of the chromosome 3 (3q26). The EVI-1 gene is scarcely expressed in normal human hematopoietic cells, but expression was found in some acute myeloblastic leukemia (AML) and MDS, with and without 3q26 abnormalities.2 Kurokawa et al3 reported that the EVI-1 protein interacts with SMAD3 protein and blocks the signal from TGF-β, and in reporter assay overexpression of the EVI-1 protein suppresses transcriptional activation of the p15 gene promoter by TGF-β in epithelial cells. These observations suggest the possibility that the ectopic expression of the EVI-1 gene may contribute to the pathogenesis of MDS by suppressing TGF-β-induced p15 gene expression. Since hypermethylation of the promoter of the p15 gene should lead to silencing of transcription, either hypermethylation of the p15 gene or expression of the EVI-1 gene should suffice to achieve unresponsiveness of the p15 gene to TGF-β stimulation. If the ectopic expression of the EVI-1 gene contributes to MDS leukemogenesis only through suppression of p15 gene expression, the expression of the EVI-1 gene and the hypermethylation of the p15 gene are expected to be found, on the level of cases, in a mutually exclusive fashion. On the other hand, if expression of the EVI-1 gene has other leukemogenic effect(s) in MDS, in addition to suppression of the p15 gene expression, these two abnormalities may more likely be found randomly in MDS cases.

These considerations prompted us to examine patients with MDS and acute leukemia evolved from MDS (sAML) for the methylation of the p15 gene and the ectopic expression of the EVI-1 gene. The bone marrow (BM) and peripheral blood (PB) cells from 34 patients (nine RA, two RARS, 10 RAEB, one CMML, seven RAEB-T, five sAML) were examined for the p15 gene by the methylation-specific PCR (MSP) method as previously described,4 and for the EVI-1 gene by two-step RT-PCR reported by Privitera et al.5 All samples were obtained with informed consent of the patients. Specific bands amplified with the methylated sequence-specific primer pair (M primers) for the p15 gene were observed in 12 patients, and nested RT-PCR with primers specific for the EVI-1 gene revealed detectable bands in nine patients. Eighteen patients showed at least one of the two abnormalities, and three patients, one with RAEB and two with sAML, showed both alteration. The results are summarized in Table 1.

Table 1 Summary of results of p15-MSP and EVI-1 RT-PCR
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References

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Authors and Affiliations

  1. Department of Clinical Research, Nagoya National Hospital, Japan

    H Ohashi, K Tsushita, M Utsumi & M Shimoyama

  2. Nagoya University School of Health Sciences, Japan

    T Murate

  3. First Department of Internal Medicine, Nagoya University School of Medicine, Japan

    T Uchida, E Aoki, H Saito & T Kinoshita

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  1. H Ohashi
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  2. K Tsushita
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  3. M Utsumi
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  6. T Uchida
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  8. H Saito
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  9. T Kinoshita
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Ohashi, H., Tsushita, K., Utsumi, M. et al. Relationship between methylation of the p15 gene in myelodysplastic syndromes (MDS). Leukemia 15, 990–991 (2001). https://doi.org/10.1038/sj.leu.2402138

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