Greek (<sup>A</sup>γ) variant of hereditary persistence of fetal haemoglobin: globin gene organization and studies of expression of fetal haemoglobins in clonal erythroid cultures

Papayannopoulou, T; Lawn, Richard M.; Stamatoyannopoulos, George; Maniatis, Tom

doi:10.1111/j.1365-2141.1982.tb01934.x

Cited by 19 publications

(2 citation statements)

References 35 publications

(9 reference statements)

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“…(5). Appropriate cell concentrations (1-3 X 105/ ml) were cultured in methylcellulose plates in the presence of erythropoietin (2 international units/ml), 10 ,uM 2-mercaptoethanol, 0.1% bovine serum albumin, and 30% (vol/vol) serum. To study the effect of fetal sheep serum, sets of duplicate cultures, one grown in the presence of fetal calf serum and the other in the presence offetal sheep serum, were used.…”

mentioning

confidence: 99%

Hemoglobin switching in culture: evidence for a humoral factor that induces switching in adult and neonatal but not fetal erythroid cells.

Papayannopoulou¹,

Kurachi²,

Nakamoto³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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An erythropoietic activity that exerts a profound effect on fetal Hb synthesis is present in fetal sheep sera and it attains a peak concentration at the end ofthe second to the middle ofthe third trimester offetal life. The activity consistently inhibits the increased synthesis of fetal Hb in cultures of burst-forming units (BFUes) from normal adults. In cultures of BFUes from homozygous fi+-thalassemias the activity produces a striking decline in ychain synthesis, a decline in Gy/Ay chain synthesis ratio, and an increase in 6/y and a/non-a ratios-i.e., findings suggesting a genuine -to-P8 switch. The activity accelerates Hb F-toHb A switching in neonatal BFUe cultures but it has no effect on fetal Hb synthesis in cultures of BFUe obtained from human fetuses. These findings provide direct evidence that (a) humoral factors play a role in the regulation of the switch from fetal to adult Hb formation, and (b) progenitor cells from various stages of ontogeny respond differently to these factors. The results are compatible with the hypothesis that Hb switching during development is mediated through a change in a developmental program which controls the responsiveness of progenitor cells to "switching" activities in their environment.tial humoral inducers of Hb switching appear in sheep fetuses before or at the time Hb switching starts. We found that sera obtained from the ontogenetic time preceding the Hb switching in sheep have a profound effect on Hb F synthesis in human adult BFUe cultures. They influence Hb F-to-Hb A switching in neonatal BFUe cultures but have no effect on fetal BFUes.These results suggest that factors in the hemopoietic environment play a role in the switching process. Our findings further show that the response of hemopoietic cells to these environmental factors depends on the stage of ontogeny from which the cells derive. The simplest interpretation of these observations is that the cellular regulation of Hb switching is mediated through qualitative changes that occur in progenitor cells; as development progresses, the progenitor cells may acquire the ability to interact with activities present in their environment and this interaction either directly or indirectly (through changes in progenitor cell differentiative programs) brings about a switch of the program of globin synthesis in the erythroid cells. (1, 5, 7). We tested whether poten- METHODSThe cells used for culture were from peripheral blood or bone marrow ofadult volunteers, from umbilical cord bloods of neonates, and from livers or fetal blood of abortuses. Peripheral blood mononuclear cells were isolated through Ficoll-sodium Metrizoate (Lymphoprep, Nyegaard, Norway) centrifugation (1). Bone marrow cells were obtained from buffy coat preparations. Fetal liver cells were prepared as a single-cell suspension from liver fragments after removal of cell aggregates and stromal pieces (5). Appropriate cell concentrations (1-3 X 105/ ml) were cultured in methylcellulose plates in the presence of erythropoietin (2 international u...

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confidence: 99%

Hemoglobin switching in culture: evidence for a humoral factor that induces switching in adult and neonatal but not fetal erythroid cells.

Papayannopoulou¹,

Kurachi²,

Nakamoto³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous in vivo observations [8] as well as studies on cultured erythroid colonies [26] strongly suggest, but do not prove, that Gy globin originates from an overexpressed Gy gene adjacent to the Greek HPFH mutant. We believe that it is very unlikely that an XmnI negative Gy gene cis to the P039-thal determinant might be overexpressed, but there is a speculative physical basis for increased Gy gene expression in cis to the *y HPFH.…”

Section: Discussionmentioning

confidence: 92%

Fetal hemoglobin expression in compound heterozygotes for −117 (G→A) ^Aγ HPFH and β⁰39 nonsense thalassemia

Pistidda¹,

Frogheri²,

Oggiano³

et al. 1995

American J Hematol

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The -117(G-->A)A gamma hereditary persistence of fetal hemoglobin (Greek HPFH) and beta zero 39-thal mutations are rather frequent in Sardinia so that their interaction is to be expected. Characterization of eight compound heterozygotes for these defects indicated that HPFH was linked to haplotype VII and beta zero 39-thal to haplotype II. Haplotype II beta zero 39-thal chromosome carries the A gamma T gene which is a useful marker of gamma-gene expression. Since the Hb F level in these compound heterozygotes was significantly higher than in 46 -117 HPFH carriers, the A gamma I, A gamma T, and G gamma globin level was determined. A gamma T was underexpressed while G gamma was significantly increased, which suggest that in -117 A gamma HPFH/beta zero 39-thal healthy subjects the increase in Hb F production is determined only by the -117 mutated A gamma gene and the adjacent G gamma gene.

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Somatic-Cell Mutation Monitoring System Based on Human Hemoglobin Mutants

Stamatoyannopoulos

Nute

Lindsley

et al. 1984

Single-Cell Mutation Monitoring Systems

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Greek (^Aγ) variant of hereditary persistence of fetal haemoglobin: globin gene organization and studies of expression of fetal haemoglobins in clonal erythroid cultures

Cited by 19 publications

References 35 publications

Hemoglobin switching in culture: evidence for a humoral factor that induces switching in adult and neonatal but not fetal erythroid cells.

Hemoglobin switching in culture: evidence for a humoral factor that induces switching in adult and neonatal but not fetal erythroid cells.

Fetal hemoglobin expression in compound heterozygotes for −117 (G→A) ^Aγ HPFH and β⁰39 nonsense thalassemia

Somatic-Cell Mutation Monitoring System Based on Human Hemoglobin Mutants

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Greek (Aγ) variant of hereditary persistence of fetal haemoglobin: globin gene organization and studies of expression of fetal haemoglobins in clonal erythroid cultures

Cited by 19 publications

References 35 publications

Hemoglobin switching in culture: evidence for a humoral factor that induces switching in adult and neonatal but not fetal erythroid cells.

Hemoglobin switching in culture: evidence for a humoral factor that induces switching in adult and neonatal but not fetal erythroid cells.

Fetal hemoglobin expression in compound heterozygotes for −117 (G→A) Aγ HPFH and β039 nonsense thalassemia

Somatic-Cell Mutation Monitoring System Based on Human Hemoglobin Mutants

Contact Info

Product

Resources

About

Greek (^Aγ) variant of hereditary persistence of fetal haemoglobin: globin gene organization and studies of expression of fetal haemoglobins in clonal erythroid cultures

Fetal hemoglobin expression in compound heterozygotes for −117 (G→A) ^Aγ HPFH and β⁰39 nonsense thalassemia