An erythroid and megakaryocytic common precursor cell line (B1647) expressing both c‐mpl and erythropoietin receptor (Epo‐R) proliferates and modifies globin chain synthesis in response to megakaryocyte growth and development factor (MGDF) but not to erythropoietin (Epo)

Bonsi, Laura; Grossi, Alberto; Strippoli, Pierluigi; Tumietto, Fabio; Tonelli, Roberto; Vannucchi, Alessandro M.; Ottolenghi, Sergio; Visconti, Giovannella; Avanzi, Gian Carlo; Pegoraro, Luigi; Bagnara, Gian Paolo

doi:10.1046/j.1365-2141.1997.2793096.x

Cited by 18 publications

(10 citation statements)

References 26 publications

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“…11 Recent data support the concept that megakaryocytic and erythrocytic cell lineages share a common precursor. 51 Multipotential 37 or bipotential 52-54 cell lines expressing Epo receptors 37,53 have been obtained in which erythroid differentiation can be induced through the action of Epo 37,52 and megakaryocytic differentiation by Tpo. 52,54 Such a bipotent erythromegakaryocytic progenitor has also been characterized in normal human bone marrow, 55 coexpressing glycophorin A and glycoprotein IIIa.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Recombinant Human Erythropoietin on Platelet Counts Is Strongly Modulated by the Adequacy of Iron Supply

Loo

Béguin

1999

Blood

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The effect of recombinant human erythropoietin (rHuEpo) on megakaryopoiesis remains controversial. Treatment with rHuEpo in renal failure patients has been associated with a slight elevation of platelet counts. In animal studies, high doses of rHuEpo produced an increase of platelet counts followed by a gradual return to normal after 7 to 15 days or even a substantial degree of thrombocytopenia. However, because iron deficiency is also known to be associated with thrombocytosis, (functional) iron deficiency during rHuEpo could be contributing to these observations. We investigated the impact of iron supply on changes in platelet counts induced by rHuEpo. Rats were either fed normal food (normal rats) or received 1% carbonyl iron for 2 weeks or 3 months, as well as during the experiment, to achieve iron supplementation or overload, respectively. Rats of all three categories then received daily intravenous injections of rHuEpo (10, 50, or 150 U) or normal saline (0 U) for 20 days. With 0 to 10 U rHuEpo, platelets remained stable. In normal rats receiving 50 to 150 U rHuEpo, platelets increased to 120% to 140% of baseline at 4 to 12 days to level off at 120% at 16 to 20 days. This response was less sustained in splenectomized animals. Iron-supplemented rats receiving 50 to 150 U rHuEpo also increased platelets initially, but the peak was at day 4, followed by a gradual return to baseline and even a moderate thrombocytopenia later on. Iron-overloaded rats receiving 50 to 150 U rHuEpo also had increased platelets at day 4, but the duration of platelet increase was shorter, and they experienced a more pronounced degree of thrombocytopenia in proportion to the dose of rHuEpo. Because the early elevation of platelets was of larger magnitude than hematocrit changes, it is unlikely that it could be accounted for by shrinkage of plasma volume. Because it was observed in all three iron conditions, there appears to be some direct positive effect of rHuEpo on platelet production. However, after this transient effect, expanded erythropoiesis appears to exert a negative impact upon platelet production. Secondary thrombocytopenia was not related to splenic pooling, and its very slow correction after cessation of rHuEpo therapy is not compatible with changes in platelet survival. Rather, it is consistent with stem cell competition between erythroid and megakaryocytic development. However, this secondary thrombocytopenia is masked by (functional) iron deficiency in rats not receiving an adequate iron supply from food or stores.

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Section: Discussionmentioning

confidence: 99%

The Effect of Recombinant Human Erythropoietin on Platelet Counts Is Strongly Modulated by the Adequacy of Iron Supply

Loo

Béguin

1999

Blood

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“…27 In addition, numerous continuous cell lines with the characteristics of a bipotent progenitor for these two lineages have been described. 28,29 Taken together with the results from targeted mutation of transcription factors as noted above, these studies strongly support the idea of a separate vascular progenitor in the hematopoietic lineage.…”

Section: A Tripartite Model Of Hematopoietic Developmentmentioning

confidence: 99%

(R)Evolutionary Considerations in Hematopoietic Development

Cooper

Spangrude

1999

Annals of the New York Academy of Sciences

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Evolutionary aspects of three characteristics of the mammalian hematopoietic system are considered in the context of both established and recent data. First, the lineage relationships among early members of the hematopoietic hierarchy are reconsidered in a tripartite model proposing lineage segregation based on vascular function, innate immunity, and acquired immunity on an evolutionary time scale. Second, the observation of two stem cell populations that differ in cell cycle status is considered as an evolved mechanism to enhance survival of the species in response to exposure to environmental toxins. Finally, the mobilization of hematopoietic stem cells into the peripheral circulation is proposed to be a mechanism for rapid dissemination of myeloid function during acute bacterial infections. These revolutionary hypotheses challenge some conventional concepts of stem cell biology, and provide an evolutionary context for considering mammalian hematopoiesis.

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“…Thrombopoietin (TPO), also known as the MPL ligand or megakaryocyte growth and development factor (MGDF), is the principal regulator of megakaryocytic cell proliferation and differentiation (Bartley et al 1994;Kaushansky et al 1994), although its action is not restricted to this hemopoietic cell lineage (Kobayashi et al 1995;Bonsi et al 1997;Brizzi et al 1997). TPO's receptor, c-mpl, belongs to the cytokine receptor superfamily (Vigon et al 1992;Mignotte et al 1994).…”

Section: Introductionmentioning

confidence: 98%

Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor ( c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT)

et al. 2000

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Congenital amegakaryocytic thrombocytopenia (CAMT) without physical anomalies is a rare disease, presenting isolated thrombocytopenia and megakaryocytopenia in infancy, which can evolve into aplastic anemia and leukemia. Recently, two heterozygous truncating mutations of the thrombopoietin (TPO) receptor MPL, coded by the c-mpl gene, were identified in a 10-year-old Japanese patient with CAMT transmitted in an autosomal recessive manner. Here, we report for the first time two different MPL amino-acid substitutions in a 2-year-old Italian boy with CAMT and compound heterozygosis for two (c-mpl point mutations. C-to-T transitions were detected on exons 5 and 12 at the 769 and 1904 cDNA nucleotide positions, respectively. The mutation in exon 5 substitutes an arginine with a cysteine (R257C) in the extracellular domain, 11 amino acids distant from the WSXWS motif conserved in the cytokine-receptor superfamily. The mutation in exon 12 substitutes a proline with a leucine (P635L) in the last amino acid of the C-terminal intracellular domain, responsible for signal transduction. As in the Japanese family, the mutations were both transmitted from the parents. TPO plasma levels were highly increased in the patient. The patient's 7-year-old brother, who was a candidate donor for allografting, turned out to be an asymptomatic heterozygous carrier of P635L and showed defective megakaryocyte colony formation from bone-marrow progenitor cells. The present study provides important confirmation that CAMT can be associated with (c-mpl) mutations.

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An erythroid and megakaryocytic common precursor cell line (B1647) expressing both c‐mpl and erythropoietin receptor (Epo‐R) proliferates and modifies globin chain synthesis in response to megakaryocyte growth and development factor (MGDF) but not to erythropoietin (Epo)

Cited by 18 publications

References 26 publications

The Effect of Recombinant Human Erythropoietin on Platelet Counts Is Strongly Modulated by the Adequacy of Iron Supply

The Effect of Recombinant Human Erythropoietin on Platelet Counts Is Strongly Modulated by the Adequacy of Iron Supply

(R)Evolutionary Considerations in Hematopoietic Development

Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor ( c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT)

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