Mechanism for fetal hemoglobin induction by hydroxyurea in sickle cell erythroid progenitors

B. Surendra Baliga, Betty S. Pace, Hsueh Hua Chen, Arvind K. Shah, Yih Ming Yang

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Hydroxyurea (HU) is a widely used cytotoxic agent that is known to induce fetal hemoglobin (HbF) production and is presently used to ameliorate the severity of pain episodes in patients with sickle cell anemia (HbSS). Previously we have shown that HU inhibits growth of burst forming unit-erythroid (BFU-E) colonies in a dose-dependent manner, while fetal hemoglobin levels were increased. In the present report, we extended our analysis demonstrating the number of S phase cells is significantly higher for HbSS patients that respond to HU therapy. Studies were completed in vitro using erythroid progenitors derived from umbilical cord samples or peripheral blood from patients with HbS-hereditary persistence of fetal hemoglobin (HbS-HPFH) or HbSS disease. The effect of HU on (a) S phase erythroid progenitors, (b) BFU-E colony growth, (c) HbF levels in BFU-E colonies, and (d) total cellular RNA synthesis was analyzed in vitro for the three groups. The level of S phase erythroid progenitors was similar for all three groups and BFU-E colony growth was inhibited 92-94% for all samples in a dose-dependent manner. The HbF levels were increased in BFU-E colonies from HbSS patients (control, 4.0% ± 1.15% vs. +HU, 22.67% ± 2.03%) whereas HbF levels were decreased in BFU-E colonies derived from umbilical cord samples (control, 80% ± 9.07% vs. +HU, 35.7% ± 4.81%) or HbS-HPFH patients (control, 49.87% ± 3.84% vs. +HU, 23.3% ± 0.88%). Total RNA synthesis measured by 3H-uridine incorporation increased with increasing concentrations of HU; however, actinomycin D inhibited HU-induced RNA synthesis. These results suggest that HU can inhibit an active globin gene without preference and that newly synthesized RNA is under transcriptional control mechanisms. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)227-233
Number of pages7
JournalAmerican Journal of Hematology
Volume65
Issue number3
DOIs
StatePublished - Oct 30 2000
Externally publishedYes

Keywords

  • BFU-E
  • Hb F
  • Hydroxyurea
  • Sickle cell anemia

ASJC Scopus subject areas

  • Hematology

Fingerprint Dive into the research topics of 'Mechanism for fetal hemoglobin induction by hydroxyurea in sickle cell erythroid progenitors'. Together they form a unique fingerprint.

  • Cite this