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[Mpl ligand (thrombopoietin) and platelet regulation]
F Wendling1, K Cohen-Solal, N Debili
1INSERM U362, Institut Gustave-Roussy, Villejuif.
Abstract:
After 35 years of research, the physiological regulator of platelet production has been isolated and its gene cloned. This discovery originates from studies performed with the myeloproliferative leukemia virus (MPLV), a murine retrovirus which induces an acute myeloproliferative syndrome in adult mice. MPLV carries in its genome the v-mpl oncogene which corresponds to a truncated form the c-mpl proto-oncogene. c-mpl encodes a cytokine receptor (Mpl-R) belonging to the hematopoietin receptor superfamily. Among the hematopoietic cell lineages, Mpl-R is preferentially expressed on late megakaryocyte progenitors, megakaryocytes and platelets. The ligand for Mpl-R, called Mpl-L or TPO or MGDF or megapoietin, is a glycosylated hormone of 352 amino acids in human which comprises two domains: the N-terminus domain shares 50% similarity with erythropoietin and is responsible for the biological activity; the C-terminus part is required for secretion. Notwithstanding its major action on megakaryocytopoiesis and thrombocytopoiesis, Mpl-L also potentiates the action of other cytokines on several hematopoietic lineages. Mpl-L/TPO/MGDF, the homeostatic regulator of platelet production, might be a useful therapeutical cytokine to treat thrombocytopenia induced in patients by chemotherapy.
Insights
Researchers have identified the key regulator of platelet production, Mpl-L (also known as TPO or MGDF), and cloned its gene. This discovery offers potential new treatments for chemotherapy-induced thrombocytopenia.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Platelet production is regulated by specific physiological factors.
- The myeloproliferative leukemia virus (MPLV) provided insights into platelet regulation.
- MPLV contains the v-mpl oncogene, linked to the c-mpl proto-oncogene.
Purpose of the Study:
- To isolate and characterize the physiological regulator of platelet production.
- To clone the gene encoding this regulator.
- To explore the therapeutic potential of this regulator for thrombocytopenia.
Main Methods:
- Studies involving the myeloproliferative leukemia virus (MPLV) in mice.
- Gene cloning of the c-mpl proto-oncogene.
- Characterization of the Mpl-R cytokine receptor and its ligand, Mpl-L.
Main Results:
- Isolated the physiological regulator of platelet production after 35 years of research.
- Cloned the gene for the regulator, identified as Mpl-L (TPO/MGDF).
- Mpl-R, the receptor for Mpl-L, is expressed on megakaryocyte progenitors, megakaryocytes, and platelets.
- Mpl-L has a domain similar to erythropoietin responsible for biological activity.
- Mpl-L potentiates other cytokine actions on hematopoietic lineages.
Conclusions:
- Mpl-L (TPO/MGDF) is the primary physiological regulator of platelet production.
- The discovery facilitates understanding of megakaryocytopoiesis and thrombocytopoiesis.
- Mpl-L/TPO/MGDF shows promise as a therapeutic agent for thrombocytopenia in chemotherapy patients.