Synthesis of hemoglobin F in adult simian erythroid progenitor-derived colonies.

Macklis, Roger M.; Javid, Jamshid; Lipton, Jeffrey M.; Kudisch, Michele; Pettis, Penelope; Nathan, David G.

doi:10.1172/jci110671

Cited by 29 publications

(12 citation statements)

References 24 publications

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“…Evaluations of these treatments in simian models, as reported here and elsewhere (3,4,25), are likely to provide important new concepts that will enhance their useful applications in the management of certain hemoglobinopathies, but determination of appropriate methods of administration will require cautious human trials.…”

Section: Resultsmentioning

confidence: 88%

“…In that report and elsewhere, we (2) and others (3) suggested that the increase in fetal hemoglobin induced by hydroxyurea and other cell cycle-dependent, phase-specific cytotoxic drugs might be due to preferential destruction of mature erythroid progenitor cells (CFU-E)' and precursors.2 This would be followed by replacement of the marrow erythroblast pool with cells immediately derived from less mature progenitors in which the fetal hemoglobin synthesis program is retained (4). This proposed switch of the origin of erythroid precursors failed, however, to account for the very rapid increment of fetal hemoglobin and F cells and the lack of reticulocytopenia following treatment of experimental animals and patients with such agents (5)(6)(7).…”

Section: Introductionmentioning

confidence: 92%

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Influence of cell cycle phase-specific agents on simian fetal hemoglobin synthesis.

Letvin¹,

Linch²,

Beardsley³

et al. 1985

J. Clin. Invest.

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To determine the influence of cell cycle-specific agents on primate hematopoiesis and fetal hemoglobin production, two juvenile cynomolgus monkeys (Macaca fascicularis) were repeatedly bled to maintain their hemoglobins at -6.5 g/dl and fetal hemoglobin levels at 3-5%. Six separate 5-d courses of hydroxyurea at 100 mg/kg per d were then administered over the next 200 d while phlebotomy was continued. These courses of hydroxyurea progressively raised the fetal hemoglobin levels to 17 and 18%, respectively. The drug had very little effect on the frequency of immature erythroid progenitors (BFU-E) in the bone marrow, but caused a marked reduction in the frequency of later progenitors (CFU-E) and a transient fall in the reticulocyte count. Following the courses of hydroxyurea, the number of F cells and the fetal hemoglobin level fell to base line over a period of 4 wk. Two control animals which were not phlebotomized showed no detectable increase in F cells or fetal hemoglobin when treated with the same regimen of hydroxyurea.A 5-d course of 5-azacytidine at 8 mg/kg per d was then given to each of the phlebotomized animals. This produced a more profound, albeit transient, reticulocytopenia, a fall in the CFU-E/BFU-E ratio, and a prompt increase in the fetal hemoglobin to levels even higher than were seen following a single 5-d course of hydroxyurea at 100 mg/kg/d. Subsequently, the animals were given a single dose of vinblastine at 0.4 mg/ kg which reduced reticulocytes and CFU-E to the same extent as hydroxyurea; however, vinblastine at this dose had no effect on hemoglobin F (HbF) production. In contrast, when vinblastine was administered to the phlebotomized monkeys as a 5-d course at 0.2 mg/kg/d, prolonged reticulocytopenia followed by dramatic F cell and HbF responses were seen. Combinations of single dose vinblastine and a 5-d course of hydroxyurea were subsequently administered using two different schedules. When the animals received vinblastine on the first day of a 5-d course of hydroxyurea, the F cell response was double that seen following hydroxyurea treatment alone. In contrast, when vinblastine was administered on the final day of hydroxyurea treatment, the magnitude of the F cell response was the same as that which occurred following hydroxyurea treatment alone, but the onset of the rise was delayed for 4 d and HbF/F cell response was much higher.Received for publication 10 These results establish several important features of the fetal hemoglobin response to cytotoxic agents in the primate model. The response requires accelerated erythropoiesis and is preceded by transient reticulocytopenia. The response is produced by S phase-and M phase-specific agents when given in sufficient doses and at appropriate schedules. Passage of erythrocyte progenitors through M phase appears to be necessary for expression of the effect produced by S phase agents. The fetal hemoglobin response induced by cytotoxic drug administration occurs during the recovery of erythropoiesis following marrow suppression.

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Section: Resultsmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 92%

Influence of cell cycle phase-specific agents on simian fetal hemoglobin synthesis.

Letvin¹,

Linch²,

Beardsley³

et al. 1985

J. Clin. Invest.

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“…Hb F .synthesis in culture is consistently increased, presumably because terminal differentiation occurs in less mature progenitors, at a time when the suppression of the Hb F program is incomplete (5,8). Factors that stimulate early BFU-E differentiation promote increased Hb F synthesis.…”

Section: Introductionmentioning

confidence: 99%

Fetal hemoglobin accumulation in vitro. Effect of adherent mononuclear cells.

Javid¹,

Pettis²

1983

J. Clin. Invest.

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“…This model is not supported by our finding of two temporally separated classes of progenitors. Failure by others to observe a bimodal distribution of Hb F in day 14 colonies is clearly not incompatible with a clonal modal in which the fetal and adult cohorts appear at different (30). This is additional evidence for discrete differences between …”

Section: Discussionmentioning

confidence: 73%

“…(Abstr. ) Received for publication 9 July 1982 and in revised form 30 November 1982. ' Abbreviations used in this paper: BFU-E, erythroid burst-forming unit; Ep, erythropoietin; Hb, hemoglobin; KRP, Krebs-Ringer phosphate buffer.…”

Section: Introductionmentioning

confidence: 99%

Switch from fetal to adult hemoglobin is associated with a change in progenitor cell population.

Weinberg¹,

Goldberg²,

Schofield³

et al. 1983

J. Clin. Invest.

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A B S T R A CT To examine the switch from fetal to adult hemoglobin at the cellular level, erythroid progenitor cells from newborn infants and adults were cultured in methyl cellulose with erythropoietin. Individual erythroid colonies were labeled with [3H]-leucine at various times, and globin synthesis patterns examined by gel electrophoresis and fluorography. The percent Ay-or fl-globin synthesis was determined from the total of y + P, and the percent Gy from the total of Gy + Ay. The nonparametric correlation coefficients of percent G-y with percent y or # were obtained. Each group of colonies at each time point was examined separately. In colonies from adult blood, the proportion of Gy-synthesis did not correlate with the proportion of y-synthesis. Colonies from newborn blood fell into two groups. Those that developed from relatively mature progenitor cells, and were seen on day 14, showed a strong negative correlation of Gy with f3-globin synthesis. However, those newborn colonies that developed from immature progenitors, and were seen later in culture (days 17 and 21), showed no correlation of Gy with A-synthesis. These findings are compatible with a clonal model for hemoglobin switching. Fetal progenitors, in which G'y-and #-syntheses are negatively correlated, are gradually replaced during ontogeny by adult progenitors. The adult progenitors produce more If (less y), and the proportions of Goy-and y-or Bi-synthesis are not correlated.

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Synthesis of hemoglobin F in adult simian erythroid progenitor-derived colonies.

Cited by 29 publications

References 24 publications

Influence of cell cycle phase-specific agents on simian fetal hemoglobin synthesis.

Influence of cell cycle phase-specific agents on simian fetal hemoglobin synthesis.

Fetal hemoglobin accumulation in vitro. Effect of adherent mononuclear cells.

Switch from fetal to adult hemoglobin is associated with a change in progenitor cell population.

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