Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy.

Abstract

Thrombopoietin (TPO), the ligand for the receptor protooncogene c-mpl, has been cloned and shown to be the critical regulator of platelet production. Several features of c-Mpl expression, including its presence on erythroid cell lines, and the panmyeloid transformation characteristic of myeloproliferative leukemia (MPL) viral disease led us to investigate whether this receptor-ligand system may play a role in erythropoiesis. We report that although TPO alone did not support the growth of either early or late erythroid progenitors, it acted in synergy with erythropoietin to expand these populations. Moreover, while the effects on erythropoiesis in normal animals were modest, TPO greatly expanded the number of erythroid progenitors and blood reticulocytes and was associated with accelerated red cell recovery in myelosuppressed mice. Together, these data strongly suggest that erythroid progenitors respond to TPO and that this newly cloned cytokine, critical for platelet production, can augment erythropoiesis in states of marrow failure. (J. Clin. Invest. 1995. 96:1683-1687

Synergistic effects on erythropoiesis, thrombopoiesis, and stem cell competitiveness in mice deficient in thrombopoietin and steel factor receptors

“…24 Moreover, while administration of Tpo to wild-type mice caused limited effects on circulating RBC content, it did increase the more primitive blast-forming unit-erythroid (BFU-E) in bone marrow and spleen. 41 Administration of the cytokine to mice with damaged erythropoietic systems had more dramatic effects at the mature cell level, rescuing the anemia in EpoR Ϫ/Ϫ mice 42 or increasing CFU-E and reticulocyte counts in myelosuppressed mice. 41 Our finding that the c-Mpl Ϫ/Ϫ Kit Wv/Wv mutations cause a more severe anemia than either single-gene mutation shows that c-Mpl does contribute to residual erythropoiesis on a Kit Wv/Wv background.…”

“…41 Administration of the cytokine to mice with damaged erythropoietic systems had more dramatic effects at the mature cell level, rescuing the anemia in EpoR Ϫ/Ϫ mice 42 or increasing CFU-E and reticulocyte counts in myelosuppressed mice. 41 Our finding that the c-Mpl Ϫ/Ϫ Kit Wv/Wv mutations cause a more severe anemia than either single-gene mutation shows that c-Mpl does contribute to residual erythropoiesis on a Kit Wv/Wv background. Thus, although the effects of Tpo signaling are restricted to primitive erythropoietic cells in normal mice, it may also contribute to mature erythropoiesis in stressed or damaged hematopoietic states.…”

The biology of thrombopoietin and thrombopoietin receptor agonists

“…Indeed, patients who develop a neutralizing antibody to thrombopoietin eventually develop pancytopenia [10,34,35].…”

The molecular and cellular biology of thrombopoietin: the primary regulator of platelet production

“…By using a competitive repopulation assay, Solar et al (1998) have con®rmed these conclusions in vivo, demonstrating that all repopulating hematopoietic stem cells express c-Mpl and that in mice nullizygous for the receptor the numbers of HSCs fall to *15% of normal (Solar et al, 1998). Thrombopoietin also a ects early erythroid progenitor cells, although only in combination with EPO (Kaushansky et al, 1995b;Kobayashi et al, 1995), and greatly a ects the development of progenitors committed to the megakaryocyte lineage Broudy et al, 1995). Thrombopoietin also leads to the maturation of megakaryocytic progenitors, giving rise to cells that express platelet speci®c cell surface proteins and display polyploidy, a manifestation of an unusual cell cycle in which late anaphase and telophase are skipped, resulting in an uncoupling of S phase and cell division.…”