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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.
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Submitted May 3, 2007
Accepted January 29, 2009
Enhanced expression of p210BCR/ABL and aberrant expression of Zfp423/ZNF423 induce blast crisis of chronic myelogenous leukemia
Kazuko Miyazaki, Norimasa Yamasaki, Hideaki Oda, Takeshi Kuwata, Yohei Kanno, Masaki Miyazaki, Yukiko Komeno, Jiro Kitaura, Zen-ichiro Honda, Soren Warming, Nancy A. Jenkins, Neal G. Copeland, Toshio Kitamura, Takuro Nakamura, and Hiroaki Honda*
Department of Developmental Biology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan
Pathology Section, Clinical Laboratory Division, National Cancer Center Hospital East, Chiba, Japan
Division of Carcinogenesis, The Cancer Institute of Japanese Foundation for Cancer Research, Tokyo, Japan
Department of Immunology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
Division of Cellular Therapy, The Institute of Medical Science, University of Tokyo, Tokyo, Japan
Department of Allergy and Rheumatology, Faculty of Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
Department of Molecular Biology, Genentech, Inc., South San Francisco, CA, United States
Cancer Genetics Laboratory, Institute of Molecular and Cell Biology, Singapore, Singapore
* Corresponding author; email: hhonda{at}hiroshima-u.ac.jp.
Chronic myelogenous leukemia (CML) is a hematopoietic disorder originating from p210BCR/ABL-transformed stem cells, which begins as indolent chronic phase (CP) but inevitably progresses into fatal blast crisis (BC). To investigate molecular mechanism(s) underlying disease evolution, CML-exhibiting p210BCR/ABL transgenic mice were subjected to retroviral insertional mutagenesis, by being crossed with BXH2 mice that transmit a replication-competent retrovirus. In contrast that non-transgenic mice in the BXH2 background exclusively developed acute myeloid leukemia after six months of age, several p210BCR/ABL transgenic littermates developed non-myeloid leukemias with a shorter latency. Inverse PCR detected two retroviral common integration sites (CISs) in tumors with B-cell phenotype. Interestingly, one CIS was transgene's own promoter, which upregulated p210BCR/ABL expression. The other was the 5' non-coding region of a transcription factor, Zfp423, which induced aberrant Zfp423 expression. The cooperative activities of Zfp423 and p210BCR/ABL were demonstrated by i) introduction of Zfp423 in p210BCR/ABL transgenic bone marrow (BM) cells increased colony-forming ability, ii) suppression of ZNF423 (human homologue of Zfp423) in ZNF423-expressing, p210BCR/ABL-positive hematopoietic cells retarded cell growth, iii) mice transplanted with BM cells transduced with Zfp423 and p210BCR/ABL developed acute leukemia, and iv) expression of ZNF423 was found in several 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.
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