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Blood, 16 July 2009, Vol. 114, No. 3, pp. 651-658. Prepublished online as a Blood First Edition Paper on May 14, 2009; DOI 10.1182/blood-2009-03-209395. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2009-03-209395v1 114/3/651    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Lin, Y.-H. Articles by Bohlander, S. K. PubMed PubMed Citation Articles by Lin, Y.-H. Articles by Bohlander, S. K. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10–positive leukemias Yi-Hui Lin1, Purvi M. Kakadia2, Ying Chen2, Ya-Qiang Li1, Aniruddha J. Deshpande2, Christian Buske2, Kang-Ling Zhang3, Yi Zhang4, Guo-Liang Xu1, and Stefan K. Bohlander2 1 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; 2 Department of Medicine III, University of Munich Hospital Grosshaden, and German Research Center for Environmental Health, Clinical Cooperative Group "Leukemia," Munich, Germany; 3 Mass Spectrometry Facility, Department of Biochemistry, School of Medicine, Loma Linda University, CA; and 4 Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill Chromosomal translocations generating fusion proteins are frequently found in human leukemias. The fusion proteins play an important role in leukemogenesis by subverting the function of one or both partner proteins. The leukemogenic CALM-AF10 fusion protein is capable of interacting with the histone H3 lysine 79 (H3K79)–specific methyltransferase hDOT1L through the fused AF10 moiety. This interaction leads to local H3K79 hypermethylation on Hoxa5 loci, which up-regulates the expression of Hoxa5 and contributes to leukemogenesis. However, the long latency of leukemogenesis of CALM-AF10 transgenic mice suggests that the direct effects of fusion oncogene are not sufficient for the induction of leukemia. In this study, we show that the CALM-AF10 fusion protein can also greatly reduce global H3K79 methylation in both human and murine leukemic cells by disrupting the AF10-mediated association of hDOT1L with chromatin. Cells with reduced H3K79 methylation are more sensitive to -irradiation and display increased chromosomal instability. Consistently, leukemia patients harboring CALM-AF10 fusion have more secondary chromosomal aberrations. These findings suggest that chromosomal instability associated with global epigenetic alteration contributes to malignant transformation in certain leukemias, and that leukemias with this type of epigenetic alteration might benefit from treatment regimens containing DNA-damaging agents. This study is registered with www.clinicaltrials.gov as NCT00266136 [ClinicalTrials.gov] . CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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