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Blood, 7 May 2009, Vol. 113, No. 19, pp. 4702-4710. Prepublished online as a Blood First Edition Paper on February 20, 2009; DOI 10.1182/blood-2007-05-088724. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2007-05-088724v1 113/19/4702    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 Citing Articles via Google Scholar Google Scholar Articles by Miyazaki, K. Articles by Honda, H. Search for Related Content PubMed PubMed Citation Articles by Miyazaki, K. Articles by Honda, H. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Enhanced expression of p210BCR/ABL and aberrant expression of Zfp423/ZNF423 induce blast crisis of chronic myelogenous leukemia Kazuko Miyazaki1, Norimasa Yamasaki1, Hideaki Oda2, Takeshi Kuwata3, Yohei Kanno4, Masaki Miyazaki5, Yukiko Komeno6, Jiro Kitaura6, Zen-ichiro Honda7, Søren Warming8, Nancy A. Jenkins9, Neal G. Copeland9, Toshio Kitamura6, Takuro Nakamura4, and Hiroaki Honda1 1 Department of Developmental Biology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; 2 Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan; 3 Pathology Section, Clinical Laboratory Division, National Cancer Center Hospital East, Chiba, Japan; 4 Division of Carcinogenesis, The Cancer Institute of Japanese Foundation for Cancer Research, Tokyo, Japan; 5 Department of Immunology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; 6 Division of Cellular Therapy, The Institute of Medical Science, University of Tokyo, Tokyo, Japan; 7 Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 8 Department of Molecular Biology, Genentech, South San Francisco, CA; and 9 Cancer Genetics Laboratory, Institute of Molecular and Cell Biology, Singapore Chronic myelogenous leukemia (CML) is a hematopoietic disorder originating from p210BCR/ABL-transformed stem cells, which begins as indolent chronic phase (CP) but progresses into fatal blast crisis (BC). To investigate molecular mechanism(s) underlying disease evolution, CML-exhibiting p210BCR/ABL transgenic mice were crossed with BXH2 mice that transmit a replication-competent retrovirus. Whereas nontransgenic mice in the BXH2 background exclusively developed acute myeloid leukemia, p210BCR/ABL transgenic littermates developed nonmyeloid leukemias, in which inverse polymerase chain reaction detected 2 common viral integration sites (CISs). Interestingly, one CIS was transgene's own promoter, which up-regulated p210BCR/ABL expression. The other was the 5' noncoding region of a transcription factor, Zfp423, which induced aberrant Zfp423 expression. The cooperative activities of Zfp423 and p210BCR/ABL were demonstrated as follows: (1) introduction of Zfp423 in p210BCR/ABL transgenic bone marrow (BM) cells increased colony-forming ability, (2) suppression of ZNF423 (human homologue of Zfp423) in ZNF423-expressing, p210BCR/ABL-positive hematopoietic cells retarded cell growth, (3) mice that received a transplant of BM cells transduced with Zfp423 and p210BCR/ABL developed acute leukemia, and (4) expression of ZNF423 was found in human BCR/ABL-positive cell lines and CML BC samples. These results demonstrate that enhanced expression of p210BCR/ABL and deregulated expression of Zfp423/ZNF423 contribute to CML BC. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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