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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 (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 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lin, Y.-H. Articles by Bohlander, S. K. Search for Related Content PubMed PubMed Citation Articles by Lin, Y.-H. Articles by Bohlander, S. K. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 9, 2009 Accepted May 6, 2009 Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10 positive leukemias Yi-Hui Lin, Purvi M. Kakadia, Ying Chen, Ya-Qiang Li, Aniruddha J. Deshpande, Christian Buske, Kang-Ling Zhang, Yi Zhang, Guo-Liang Xu, and Stefan K. Bohlander* State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China Department of Medicine III, University of Munich Hospital Grosshaden, and GSF-National Research Center for Environmental Health, Clinical Cooperative Group "Leukemia", Munich, Germany Mass Spectrometry Facility, Department of Biochemistry, School of Medicine, Loma Linda University, Loma Linda, CA, United States Howard Hughes Medical Institute, Department of Biochemistry & Biophysics, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, United States * Corresponding author; email: stefan.bohlander{at}med.uni-muenchen.de. 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. And this interaction leads to local H3K79 hypermethylation on Hoxa5 loci, which upregulates 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 leukaemia. Here 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 on www.clinicaltrials.gov under NCT00266136. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Liu, Y. Lin, A. Darwanto, X. Song, G. Xu, and K. Zhang Identification and Characterization of Propionylation at Histone H3 Lysine 23 in Mammalian Cells J. Biol. Chem., November 20, 2009; 284(47): 32288 - 32295. [Abstract] [Full Text] [PDF]

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