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Blood, 15 April 2002, Vol. 99, No. 8, pp. 3005-3013
RED CELLS
Fetal and adult hemoglobin production during adult
erythropoiesis: coordinate expression correlates with cell
proliferation
Urszula Wojda,
Pierre Noel, and
Jeffery L. Miller
From the Laboratory of Chemical Biology, National
Institute of Diabetes and Digestive and Kidney Diseases, and Laboratory
Medicine Department, Hematology Service, National Institutes of Health,
Bethesda, MD.
The design and evaluation of therapies for the sickle cell and
 -thalassemia syndromes rely on our understanding of hemoglobin accumulation during human erythropoiesis. Here we report direct measurements of hemoglobin composition and messenger RNA (mRNA) levels
in cultured CD34+ cells and correlate those measurements
with studies of freshly obtained bone marrow samples. Hemoglobin levels
in differentiating cells were also compared with morphologic,
immunophenotypic, and cell cycle assessments. A population of large
preproerythroblasts was first identified within 24 hours and became the
dominant population by day 5. The transition from proerythroblast to
basophilic normoblast occurred later, from days 7 to 9, and correlated
with a peak of 74.1% ± 3.9% of the cells in the S phase of cell
cycle. Orthochromatic normoblasts were the dominant and final cell type
by day 13. High-performance liquid chromatography-based
quantitation of fetal (HbF) and adult (HbA) hemoglobin and real-time
polymerase chain reaction globin mRNA quantitation demonstrated a
coordinate rise in the accumulation of both proteins and mRNA among
these developmentally staged populations. Quantitative analyses on
freshly sorted bone marrow populations demonstrated a similar rising
pattern with -globin and HbA as the dominant species at both early
and late stages of differentiation. We found no evidence for HbF
dominant populations or switching during differentiation in adult
cells. Instead, rapid increases in both HbF (heterocellular) and HbA
(pancellular) content were observed, which coincided with the apex in
cell cycling and the proerythroblast-basophilic normoblast transition.
Based on these measurements, we conclude that HbF and HbA content are
regulated with the rate of proliferation during adult erythropoiesis.
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