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Prepublished online as a Blood First Edition Paper on October 3, 2002; DOI 10.1182/blood-2002-01-0309.
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Blood, 1 February 2003, Vol. 101, No. 3, pp. 1188-1193
RED CELLS
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
From the Departments of Molecular Diagnostics,
Rheumatology and Hematology, and Molecular Biology, Tohoku University
School of Medicine, Sendai, Japan; Center for
Tsukuba Advanced Research Alliance, University of Tsukuba,
Japan, and Rockefeller University, New York, NY.
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, embryonic stem (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 15 times more nonheme 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.
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