Thrombocytopenia in c-mpl-deficient mice

Abstract

Thrombopoietin (TPO) is a cytokine that is involved in the regulation of platelet production. The receptor for TPO is c-Mpl. To further investigate the role and specificity of this receptor in regulating megakaryocytopoiesis, c-mpl-deficient mice were generated by gene targeting. The c-mpl-/- mice had an 85 percent decrease in their number of platelets and megakaryocytes but had normal amounts of other hematopoietic cell types. These mice also had increased concentrations of circulating TPO. These results show that c-mpl specifically regulates megakaryocytopoiesis and thrombopoiesis through activation by its ligand TPO.

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

“…At the mature cell level, mutations in c-Mpl and Kit affect the thrombopoietic and erythropoietic lineages, respectively. 7,15,22,23 Moreover, although most other mature lineages are not affected in either single mutant, they both have deficiencies at the stem cell level. 8,[16][17][18]24 We demonstrate here, in double-mutant c-Mpl Ϫ/Ϫ Kit Wv/Wv mice, which lack both Tpo and SF receptors, that these 2 cytokine pathways contribute overlapping and nonredundant actions in mature and multipotential hematopoietic compartments.…”

“…20,21 Tpo or c-Mpl knock-out mice have severe thrombocytopenia, with an 80% reduction in the number of circulating platelets. 7,22,23 c-Mpl Ϫ/Ϫ mice also have decreased numbers of clonogenic progenitor cells in multiple lineages and approximately 7-fold reduced competitive repopulation ability. 8,24 Tpo alone supports HSC survival in vitro 25,26 and acts synergistically with other early-acting factors to induce HSC division.…”

Major effects of TPO delivered by a single injection of a recombinant adenovirus on prevention of septicemia and anemia associated with myelosuppression in mice: risk of sustained expression inducing myelofibrosis due to immunosuppression

“…Indeed, homozygous TPO or c-mpl knock-out mice exhibit a profound but not lethal thrombocytopenia. 5,6 In vitro and in vivo experiments have shown that TPO is the most potent growth factor for megakaryocyte (MK) differentiation, acting on different developmental stages including MK progenitors, promegakaryoblasts and MK. 7,8 Daily TPO injection to animals including mice and primates increased platelet count up to 10-fold the control value in a few days.…”

Thrombopoietin, c‐Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists‐induced aggregation in platelets in vitro

“…Recently, several groups [2][3][4][5] cloned the ligand for the c-Mpl proto-oncogene [6] which is a member of the cytokine receptor superfamily. These studies and others have demonstrated that c-Mpl ligand plays a critical role in megakaryocytopoiesis and thrombopoiesis both in vitro and in vivo [2][3][4][5][7][8][9][10]. Therefore, c-Mpl ligand has been termed thrombopoietin (TPO) [3,7,8] or megakaryocyte growth and development factor (MGDF) [4].…”