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Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia

Leukemia volume 17, pages 1813–1819 (2003)Cite this article

Abstract

The p14ARF, p15INK4B, and p16INK4A genes are important negative cell-cycle regulators often inactivated by deletions, mutations, or hypermethylation in malignancy. Hypermethylation of the three genes was studied in 81 patients with therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) by methylation-specific PCR, and p15 methylation additionally by bisulfite genomic sequencing. In all, 55 patients disclosed p15 methylation, five patients showed p16 methylation, whereas p14 methylation was not observed. Methylation of p15 was closely associated with deletion or loss of chromosome arm 7q (P=0.0006). In t-MDS, the p15 methylation frequency and the p15 methylation density both increased significantly by stage (P=0.004 and 0.0002), and p15 methylation frequency increased with an increasing percentage of myeloblasts in the bone marrow (P=0.006). In a two-variable Cox model including the percentage of myeloblasts, p15 methylation was an independent prognostic factor (P=0.005). Methylation of p15 was less common in t-AML of subtype M5 than in other FAB subtypes (P=0.03). Methylation of p15 was unrelated to type of previous therapy, to latent period from start of therapy, to platelet count, and to p53 mutations. Inactivation of p15 and deletion of genes on chromosome arm 7q possibly cooperate in leukemogenesis.

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Acknowledgements

We are indebted to Ms Helle Thrane for technical assistance in the molecular studies. Furthermore, we thank MS Severin Larsen Olsen for his help in the statistical calculations and Professor Flemming Skovby for his help in preparing the manuscript. This work was supported by grants from the Danish Cancer Society and HS forskningspulje 1997.

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  1. Department of Clinical Genetics, Section of Hematology/Oncology, Cytogenetic Laboratory, Juliane Marie Center, Rigshospitalet, Blegdamsvej, Copenhagen Ø, Denmark

    D H Christiansen, M K Andersen & J Pedersen-Bjergaard

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Christiansen, D., Andersen, M. & Pedersen-Bjergaard, J. Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 17, 1813–1819 (2003). https://doi.org/10.1038/sj.leu.2403054

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