SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on October 3, 2002; DOI 10.1182/blood-2002-01-0309. This Article Full Text (PDF) All Versions of this Article: 2002-01-0309v1 101/3/1188    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 Harigae, H. Articles by Sassa, S. Search for Related Content PubMed PubMed Citation Articles by Harigae, H. Articles by Sassa, S. Social Bookmarking                   What's this? Submitted January 31, 2002 Accepted August 30, 2002 Aberrant iron accumulation and oxidized status of erythroid-specific -aminolevulinate synthase (ALAS2)-deficient definitive erythroblasts Hideo Harigae*, Osamu Nakajima, Naruyoshi Suwabe, Hisayuki Yokoyama, Kazumichi Furuyama, Takeshi Sasaki, Mitsuo Kaku, Masayuki Yamamoto, and Shigeru Sassa Department of Molecular Diagnostics, Tohoku University School of Medicine, Sendai, Japan Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan Department of Rheumatology and Hematology, Tohoku University School of Medicine, Sendai, Japan Department of Molecular Biology, Tohoku University School of Medicine, Sendai, Japan Department of Biochemical Hematology, The Rockefeller University, New York, NY, USA * Corresponding author; email: harigae{at}mail.cc.tohoku.ac.jp. Alas2 encodes the erythroid-specific -aminolevulinate synthase (ALAS2 or ALAS-E), the first enzyme in heme biosynthesis in erythroid cells. Mice with the Alas2-null phenotype showed massive cytoplasmic, but not mitochondrial, iron accumulation in their primitive erythroblasts. Because these animals died by day 11.5 in utero , studies of iron metabolism in definitive erythroblasts were not possible using the in vivo model. In this study, ES cells lacking the Alas2 gene were induced to undergo differentiation to the definitive erythroblast stage in culture, and the phenotype of Alas2-null definitive erythroblasts was examined. Alas2-null definitive erythroblasts cell pellets were entirely colorless due to a marked deficiency of heme, although their cell morphology was similar to that of the wild-type erythroblasts. The level of expression of erythroid-specific genes in Alas2-null definitive erythroblasts was also similar to that of the wild-type erythroblasts. These findings indicate that Alas2-null definitive erythroblasts developed to a stage similar to that of the wild-type erythroblasts, which were also shown to be very similar to the bone marrow erythroblasts in vivo. In contrast, Alas2-null definitive erythroblasts contained fifteen times more non-heme iron than did the wild-type erythroblasts, and electron microscopy found this iron to be distributed in the cytoplasm, but not in mitochondria. Consistent with the aberrant increase in iron, Alas2-null definitive erythroblasts were more peroxidized than wild-type erythroblasts. These findings suggest that ALAS2 deficiency itself does not interfere with the development of definitive erythroid cells, but it results in a profound iron accumulation and a peroxidized state in erythroblasts. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Tian, D. R. Campagna, L. S. Woodward, M. J. Justice, and M. D. Fleming hem6: an ENU-induced recessive hypochromic microcytic anemia mutation in the mouse Blood, November 15, 2008; 112(10): 4308 - 4313. [Abstract] [Full Text] [PDF] C. Pondarre, D. R. Campagna, B. Antiochos, L. Sikorski, H. Mulhern, and M. D. Fleming Abcb7, the gene responsible for X-linked sideroblastic anemia with ataxia, is essential for hematopoiesis Blood, April 15, 2007; 109(8): 3567 - 3569. [Abstract] [Full Text] [PDF] O. Nakajima, S. Okano, H. Harada, T. Kusaka, X. Gao, T. Hosoya, N. Suzuki, S. Takahashi, and M. Yamamoto Transgenic rescue of erythroid 5-aminolevulinate synthase-deficient mice results in the formation of ring sideroblasts and siderocytes Genes Cells, June 1, 2006; 11(6): 685 - 700. [Abstract] [Full Text] [PDF] J. S. Tan, N. Mohandas, and J. G. Conboy High frequency of alternative first exons in erythroid genes suggests a critical role in regulating gene function Blood, March 15, 2006; 107(6): 2557 - 2561. [Abstract] [Full Text] [PDF] K. Maki, T. Yamagata, T. Asai, I. Yamazaki, H. Oda, H. Hirai, and K. Mitani Dysplastic definitive hematopoiesis in AML1/EVI1 knock-in embryos Blood, September 15, 2005; 106(6): 2147 - 2155. [Abstract] [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020