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Locus control region-A gamma transgenic mice: a new model for studying the
induction of fetal hemoglobin in the adult
P Constantoulakis, B Josephson, L Mangahas, T Papayannopoulou, T Enver, F Costantini and G Stamatoyannopoulos
Department of Medicine, University of Washington, Seattle 98195.
All pharmacologic agents that induce fetal hemoglobin (Hb) have been
discovered with in vivo studies of humans, macaques, and baboons. We tested
whether transgenic mice carrying human fetal (gamma) globin genes provide a
model for studying the pharmacologic induction of HbF in the adult. In
initial studies, phenylhydrazine-induced hemolytic anemia, 5-azacytidine,
butyrate, or combinations of these treatments failed to activate the human
gamma-globin gene in a transgenic mouse line carrying a 4.4-kb G gamma
globin gene construct that is expressed only in the embryonic stage of
mouse development. Subsequently, adult mice carrying the human A gamma gene
linked to the locus control region (LCR) regulatory sequences and
expressing heterocellularly HbF (about 25%, gamma-positive cells) were
used. Treatments with erythropoietin, 5- azacytidine, hydroxyurea, or
butyrate resulted in induction of gamma gene expression as documented by
measurement of F-reticulocytes, the gamma/gamma + beta biosynthetic ratio
and the level of steady state gamma mRNA. Administration of erythropoietin
or butyrate to transgenic mice carrying a muLCR-beta (human) globin
construct, failed to increase human beta-globin expression. These results
suggest that the muLCR-A gamma transgenic mice provide a new model for
studying the induction of fetal Hb in the adult.
Volume 77,
Issue 6,
pp. 1326-1333,
03/15/1991
Copyright © 1991 by The American Society of Hematology
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