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Hypermethylation of the Ink4b locus in murine myeloid leukemia and increased susceptibility to leukemia in p15Ink4b-deficient mice

Oncogene volume 22, pages 9265–9274 (2003)Cite this article

Abstract

The Ink4b gene (Cdkn2b) encodes p15Ink4b, a cyclin-dependent kinase inhibitor. It has been implicated in playing a role in the development of acute myeloid leukemia (AML) in man, since it is hypermethylated with high frequency. We provide evidence that the gene is a tumor suppressor for myeloid leukemia in mice. The evidence is twofold: (1) retrovirus-induced myeloid leukemias of the myelomonocytic phenotype were found to have hypermethylation of the 5′ CpG island of the Ink4b gene, and this could be correlated with reduced mRNA expression, as demonstrated by TaqMan real-time PCR. p15Ink4b mRNA expression in a leukemia cell line, with hypermethylation at the locus, was induced following treatment with 5-aza-2′-deoxycytidine. (2) Targeted deletion of one allele in mice by removal of exon 2 increases their susceptibility to retrovirus-induced myeloid leukemia. Mice deficient in both alleles were not more susceptible to myeloid disease than those deficient in one allele, raising the possibility that there are opposing forces related to the development of myeloid leukemia in Ink4b null mice.

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Acknowledgements

We thank Miriam Anver for her expert assistance in diagnosing the leukemias, Elise Bowman for help running the real-time PCR assays, and Ricardo Dreyfuss for excellent preparation of photographic depictions of tissues and cells.

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Author notes

  1. Wei Liao

    Present address: Department of Microbiology and Immunology Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA

  2. Juraj Bies: On leave from the Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovak Republic

Authors and Affiliations

  1. Center for Cancer Research, National Cancer Institute, NIH, Bethesda, 20892-4255, MD, USA

    Linda Wolff, Matthew T Garin, Richard Koller, Juraj Bies & Wei Liao

  2. Centro Nacional De Investigaciones Oncologicas, Madrid, E-28029, Spain

    Marcos Malumbres

  3. SAIC Frederick, National Cancer Institute, MD, USA

    Lino Tessarollo & Christine Perella

  4. Data Management Services, National Cancer Institute at Frederick, Frederick, USA

    Douglas Powell

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  1. Linda Wolff
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Correspondence to Linda Wolff.

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Wolff, L., Garin, M., Koller, R. et al. Hypermethylation of the Ink4b locus in murine myeloid leukemia and increased susceptibility to leukemia in p15Ink4b-deficient mice. Oncogene 22, 9265–9274 (2003). https://doi.org/10.1038/sj.onc.1207092

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