Genetic Relationship between Fetal Hb Levels in Normal and Erythropoietically Stressed Baboons

Abstract

Previous studies have shown that the magnitude of the fetal haemoglobin (Hb F) response to haemolytic anaemia and hypobaric hypoxia in the baboon is specific to an animal ('high and low Hb F responders'), suggesting that the Hb F response is under genetic control. In this study Hb F levels in 55 adult (over 8 years old) and 23 juvenile unstressed baboons varied between 0.02% and 0.6% ('resting Hb F levels'). Twenty-nine of these animals were subjected to haemolytic stress and the magnitude of their Hb F response was positively correlated with the resting Hb F levels. In addition, the resting levels of Hb F in parents were positively correlated with those of their offspring. In 11 animals, seven adults and four juveniles, subjected to haemopoietic stress the Hb F levels were increased proportionally to the number of F-cells. In juvenile animals the calculated concentration of Hb F per F-cell was markedly higher than in adult animals. These data demonstrate that the resting level of Hb F is predictive of the magnitude of the Hb F response to stress erythropoiesis. The number of F-cells and the concentration of Hb F per cell in erythropoietic stress appear to be modulated by different mechanisms.

5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons.

“…During the period of bleeding alone (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15], maximal Hb F levels in the high and low responders were 10% and 2%, respectively. Five to 7 days after the initiation of treatment with 5-azaC, Hb F levels started to increase and reached their peaks 5-7 days after discontinuation of the drug.…”

“…METHODS Initially, four baboons (2, 3, 3, and 5 years old; weight 4-12 kg) were bled to reduce the packed erythrocyte volume (PCV) to 20% within 5 days. Two of the baboons -had been found to be high Hb F responders and two were low responders (10,11). The PCV of20% was maintained for another 10 days by bleeding; during this time, Hb F levels were measured every day by alkali denaturation (12) to determine the extent ofHb F increase in each animal due to bleeding alone.…”

“…We have chosen to use this agent in vivo in the baboon because this animal is a suitable model for the study of normal hemoglobin switching (6) and also because the reverse switch in the adult baboon has been shown to respond to erythropoietic stress with an increase in the number of Hb F-containing erythrocytes (F cells) and an increase in Hb F synthesis (7)(8)(9). The magnitude of this response (high or low) has been shown to be genetically determined (10,11) and it appeared to be of interest to determine whether these genetic differences could be influenced by 5-azaC. Other myelosuppressive agents [hydroxyurea and 1-f3-D-arabinofuranosylcytosine (araC, cytosine arabinoside)] were used in four, baboons to test their effect on Hb F synthesis.…”

HIF–prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques

“…11 In young baboons, significant increases in HbF levels occurred after phenylhydrazine induced hemolysis or hypobaric hypoxia. 12 While the magnitude of the HbF response may be genetically determined, 13 HbF levels could be maintained longterm by continued erythropoietic stress. 14 Indeed, a relationship between the HIF pathway and HbF expression has been proposed recently, and putative HIF-binding sites have been described in the locus control region of the globin gene cluster.…”

Pharmacologic Induction of Fetal Hemoglobin Synthesis: Cellular and Molecular Mechanisms

“…The best example is the increase of Hb F synthesis in the process of accelerated red blood cell maturation [12][13][14][15][16][17][18][19][20][21]. Temporary increases in Hb F production have been observed in situations in which red blood cell production rises acutely and rapidly such as compensation for acute hemolysis [18,22] ; during the recovery phase of blood loss and transient erythroblastopenia of childhood [16] ; in response to iron therapy for iron de ciency anemia [15] ; and following engraftment of transplanted bone marrow [12]. The process of rapid regeneration of red blood cells, known as stress hematopoiesis, may involve recruitment of early erythroid progenitors that have retained their c globin gene expression capacity ( Figure 2 ) [21,23,24].…”