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Blood, 15 January 2006, Vol. 107, No. 2, pp. 698-707.
Prepublished online as a Blood First Edition Paper on September 15, 2005; DOI 10.1182/blood-2005-03-1278.
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Submitted March 29, 2005
Accepted August 31, 2005
Induction of tumor arrest and differentiation with prolonged survival by intermittent hypoxia in a mouse model of acute myeloid leukemia
Wei LIU, Meng GUO, Ya-Bei XU, Li DAO, Zhao-Nian ZHOU, Ying-Li WU, Zhu CHEN, Scott C KOGAN, and Guo-Qiang CHEN*
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education of China, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine (SJU-SM, formerly Shanghai Second Medical University), Shanghai, China
Health Science Institute, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Laboratory of Hypoxia Physiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
Comprehensive Cancer Center and Department of Laboratory Medicine, University of California, San Francisco, CA, USA
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education of China, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine (SJU-SM, formerly Shanghai Second Medical University), Shanghai, China; Health Science Institute, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
* Corresponding author; email: chengq{at}shsmu.edu.cn;gqchen@sibs.ac.cn.
We showed previously that mild real hypoxia and hypoxia mimetic-agents induced in vitro cell differentiation of acute myeloid leukemia (AML). We here investigate the in vivo effects of intermittent hypoxia on syngenic grafts of leukemic blasts in a PML-RAR transgenic mouse model of AML. For intermittent hypoxia, leukemic mice were housed into a hypoxia chamber equivalent to an altitude of 6000m for 18 hours every consecutive day. The results show that intermittent hypoxia significantly prolongs the survival of the transplanted leukemic mice, although it fails to cure the disease. By histological and cytological analyses, intermittent hypoxia is shown to inhibit the infiltration of leukemic blasts in peripheral blood, bone marrow, spleen and liver without apoptosis induction. More intriguingly, intermittent hypoxia also induces leukemic cells to undergo differentiation with progressive increase of hypoxia-inducible factor-1 protein, as evidenced by morphological criteria of maturating myeloid cells and increased expression of mouse myeloid cell differentiation-related antigens Gr-1 and Mac-1. Taken together, this study represents the first attempt to characterize the in vivo effects of hypoxia on an AML mouse model. Additional investigations may uncover ways to mimic the differentiative effects of hypoxia in a manner that will benefit human patients with AML.
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