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Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia

Nature Genetics volume 37, pages 265–274 (2005)Cite this article

Abstract

DNA methylation is associated with malignant transformation, but limitations imposed by genetic variability, tumor heterogeneity, availability of paired normal tissues and methodologies for global assessment of DNA methylation have limited progress in understanding the extent of epigenetic events in the initiation and progression of human cancer and in identifying genes that undergo methylation during cancer. We developed a mouse model of T/natural killer acute lymphoblastic leukemia that is always preceded by polyclonal lymphocyte expansion to determine how aberrant promoter DNA methylation and consequent gene silencing might be contributing to leukemic transformation. We used restriction landmark genomic scanning with this mouse model of preleukemia reproducibly progressing to leukemia to show that specific genomic methylation is associated with only the leukemic phase and is not random. We also identified Idb4 as a putative tumor-suppressor gene that is methylated in most mouse and human leukemias but in only a minority of other human cancers.

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Figure 1: RLGS analysis.
Figure 2: Promoter methylation and expression of Idb4.
Figure 3: Promoter hypermethylation silences expression of Idb4.
Figure 4: Promoter methylation and expression of ID4 in human cancer.
Figure 5: Idb4 has functional characteristics of a tumor-suppressor gene.
Figure 6: Ectopic expression of Idb4 induces apoptosis in Yac-1 cells.

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Acknowledgements

We thank S. Liyanarachchi for statistical help. This work was supported in part by grants from the US Public Health Service (to C.P. and M.A.C.). C.P. and J.B. are Leukemia and Lymphoma Society of America Scholars.

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Author notes

  1. Michael A Caligiuri and Christoph Plass: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology/Oncology, Internal Medicine, The Ohio State University, Columbus, Ohio, USA

    Li Yu, Chunhui Liu, Jeff Vandeusen, Brian Becknell, Wei Ding, Charlene Mao, Shujun Liu, Guido Marcucci, John Byrd & Michael A Caligiuri

  2. Department of Hematology, 301 General Hospital of PLA, Beijing, China

    Li Yu

  3. Division of Human Cancer Genetics, Molecular Virology, Immunology, and Medical Genetics, Tzagournis Medical Research Facility 464A, 420 West 12th Ave., The Ohio State University, Columbus, 43210, Ohio, USA

    Li Yu, Chunhui Liu, Zunyan Dai, Yue-Zhong Wu, Aparna Raval, Te-Hui Liu, Laura T Smith, Stephen Lee, Michael A Caligiuri & Christoph Plass

  4. Division of Hematology/Oncology, Department of Medicine, University of California, San Diego, California, USA

    Laura Rassenti

  5. The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA

    Guido Marcucci, John Byrd, Michael A Caligiuri & Christoph Plass

  6. The Cancer and Leukemia Group B, Chicago, Illinois, USA

    Guido Marcucci, John Byrd, Michael A Caligiuri & Christoph Plass

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Correspondence to Christoph Plass.

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Supplementary information

Supplementary Fig. 1

Mouse RLGS master profile for enzyme combination NotI-EcoRV-HinfI. (PDF 4606 kb)

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Yu, L., Liu, C., Vandeusen, J. et al. Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nat Genet 37, 265–274 (2005). https://doi.org/10.1038/ng1521

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