Relationship Between Cell‐Cycle State of Erythroid Progenitors and Fetal Hemoglobin Synthesis

Isoyama, Keiichi; Baliga, Surendra; Shah, Arvind; Mankad, Vipul N.

doi:10.1002/ajh.2830390115

Cited by 3 publications

(5 citation statements)

References 7 publications

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“…Previously, we demonstrated a strong inverse linear relationship between the number of BFU-E colonies and the percent of HbF [13]. Our laboratory reported a similar inverse relationship between HbF levels and circulating S phase erythroid progenitors or BFU-E colonies in HbSS patients treated with HU [14].…”

Section: Introductionsupporting

confidence: 84%

“…The Kleinhauer-Betke stain showed an even distribution for all HbS-HPFH patients studied. The S phase cells were measured by 3 H-TDR suicide test as described above [13]. The percentage of S phase cells was not significantly different for the three samples studied (cord, 73.0 ± 3.22; HbS-HPFH, 62.0 ± 10.26; SS, 52.7 ± 4.43).…”

Section: S Phase Determinations For Mononuclear Cells Isolated From Hsupporting

confidence: 78%

“…Mononuclear cells were isolated by density centrifugation using Histopaque-1077 (Sigma Bio-chemicals Co., St. Louis, MO) as described previously [13]. The mononuclear cells were subsequently washed with Iscove's Modified Dulbecco's Media (IMDM) containing 30% fetal bovine serum (Atlanta Biological Inc., Norcross, GA), 2 mM glutamine, and 10 −4 M ␤-mercaptoethanol.…”

Section: Cell Culture Assays For Erythroid Progenitorsmentioning

confidence: 99%

“…The 3 H-thymidine ( 3 H-TDR) suicide test was performed using a modified technique described by Becker and co-workers [15] previously established by our laboratory [13] to measure DNA synthesis in erythroid progenitors. Two aliquots of the mononuclear cells (5 × 10 6 cells/ml) were taken.…”

Section: H-thymidine Suicide Testmentioning

confidence: 99%

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

et al. 2000

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Hydroxyurea (HU) is a widely used cytotoxic agent that is known to induce fetal hemo-globin (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, 49.67% ± 3.84% vs. +HU, 23.3% ± 0.88%). Total RNA synthesis measured by 3 H-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. Am.

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Section: Introductionsupporting

confidence: 84%

Section: S Phase Determinations For Mononuclear Cells Isolated From Hsupporting

confidence: 78%

Section: Cell Culture Assays For Erythroid Progenitorsmentioning

confidence: 99%

Section: H-thymidine Suicide Testmentioning

confidence: 99%

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

et al. 2000

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“…3). The link between erythropoiesis and cell cycle arrest has been shown by a number of earlier studies indicating that S-phase progression is synchronized with several rapid committal differentiation stages [30]. Specifically, the erythroid transition from pro-erythroblast to basophilic normoblast is accompanied by S-arrest [31].…”

Section: Discussionmentioning

confidence: 99%

Carbon Monoxide Induced Erythroid Differentiation of K562 Cells Mimics the Central Macrophage Milieu in Erythroblastic Islands

Toobiak

Shaklai

2012

PLoS ONE

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Growing evidence supports the role of erythroblastic islands (EI) as microenvironmental niches within bone marrow (BM), where cell-cell attachments are suggested as crucial for erythroid maturation. The inducible form of the enzyme heme oxygenase, HO-1, which conducts heme degradation, is absent in erythroblasts where hemoglobin (Hb) is synthesized. Yet, the central macrophage, which retains high HO-1 activity, might be suitable to take over degradation of extra, harmful, Hb heme. Of these enzymatic products, only the hydrophobic gas molecule - CO can transfer from the macrophage to surrounding erythroblasts directly via their tightly attached membranes in the terminal differentiation stage. Based on the above, the study hypothesized CO to have a role in erythroid maturation. Thus, the effect of CO gas as a potential erythroid differentiation inducer on the common model for erythroid progenitors, K562 cells, was explored. Cells were kept under oxygen lacking environment to mimic BM conditions. Nitrogen anaerobic atmosphere (N 2 A) served as control for CO atmosphere (COA). Under both atmospheres cells proliferation ceased: in N 2 A due to cell death, while in COA as a result of erythroid differentiation. Maturation was evaluated by increased glycophorin A expression and Hb concentration. Addition of 1%CO only to N 2 A, was adequate for maintaining cell viability. Yet, the average Hb concentration was low as compared to COA. This was validated to be the outcome of diversified maturation stages of the progenitor's population. In fact, the above scenario mimics the in vivo EI conditions, where at any given moment only a minute portion of the progenitors proceeds into terminal differentiation. Hence, this model might provide a basis for further molecular investigations of the EI structure/function relationship.

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Relationship of burst‐forming‐unit‐erythroid progenitors and their DNA‐synthesis stage to fetal hemoglobin levels in hydroxyurea‐treated patients with sickle cell anemia

et al. 1994

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DNA-synthesis stage and total number of circulating burst-forming-units-erythroid (BFU-E) have been inversely correlated with hemoglobin F levels in the peripheral blood, as well as in the cells from the BFU-E-derived colonies obtained from homozygous sickle cell anemia (SS) patients during steady state. Similar studies in SS patients treated with cytotoxic agents have not been reported. However, regeneration of the erythroid marrow that follows the cytoreduction phase of chemotherapy has been suggested as one of the mechanisms of stimulation of fetal hemoglobin synthesis. Therefore, a longitudinal study of hemopoiesis in hydroxyurea-treated SS patients was conducted. Thirty-two sets of hemopoietic studies, including total circulating BFU-E and S-phase BFU-E, were obtained from three patients treated with hydroxyurea. A dose-dependent decrease in total BFU-E colonies occurred in peripheral blood of all three patients (r = -0.58, -0.85, and -0.97, respectively, with each P < 0.05). There was a strong positive correlation between hydroxyurea dose and fetal hemoglobin levels in two of the three patients who responded clinically (r = 0.89618 and 0.88632, respectively, with each P < 0.01). When data from all patients were combined (n = 32), there was a strong, inverse, linear relationship between total number of BFU-E and percentage S-phase BFU-E with fetal hemoglobin levels (r = -0.6649 and -0.7404, respectively, with each P < 0.0001). A stronger, curvilinear, multiple relationship was detected between total BFU-E and percentage S-phase BFU-E with fetal hemoglobin levels (R = 0.8351 and 0.8602 with each P < 0.0001).

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Relationship Between Cell‐Cycle State of Erythroid Progenitors and Fetal Hemoglobin Synthesis

Cited by 3 publications

References 7 publications

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

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

Carbon Monoxide Induced Erythroid Differentiation of K562 Cells Mimics the Central Macrophage Milieu in Erythroblastic Islands

Relationship of burst‐forming‐unit‐erythroid progenitors and their DNA‐synthesis stage to fetal hemoglobin levels in hydroxyurea‐treated patients with sickle cell anemia

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