Thrombopoietin from beginning to end

Abstract

SummaryIn the two decades since its cloning, thrombopoietin (TPO) has emerged not only as a critical haematopoietic cytokine, but also serves as a great example of bench-to-bedside research. Thrombopoietin, produced by the liver, is the primary regulator of megakaryocyte progenitor expansion and differentiation. Additionally, as TPO is vital for the maintenance of haematopoietic stem cells, it can truly be described as a pan-haematopoietic cytokine. Since recombinant TPO became available, the molecular mechanisms of TPO function have been the subject of extensive research. Via its receptor, c-Mpl (also termed MPL), TPO activates a wide array of downstream signalling pathways, promoting cellular survival and proliferation. Due to its central, non-redundant role in haematopoiesis, alterations of both the hormone and its receptor contribute to human disease; congenital and acquired states of thrombocytosis and thrombocytopenia and aplastic anaemia as a result from dysregulated TPO expression or functional alterations of c-Mpl. With TPO mimetics now in clinical use, the story of this haematopoietic cytokine represents a great success for biomedical research.Keywords: thrombopoeitin, megakaryocytes, megakaryocytopoiesis, myeloproliferative disease. HistoryThe term erythropoietin (EPO) was first used in the literature in 1906 to describe the humoral substance responsible for erythropoiesis. At the time, blood platelets were barely distinguishable in the best microscopes, prompting their description with the pejorative phrase 'the dust of the blood'. However, the work of Carnot and of Wright and others in the early 20th century defined the critical role of blood platelets in coagulation and their origin from the marrow megakaryocyte, ultimately leading Kelemen and Tanos (1958) to coin the term thrombopoietin (TPO, also termed THPO) to describe the humoral substance responsible for platelet production.In the mid-1960s, several groups began attempting to purify TPO from the plasma of thrombocytopenic animals. These early efforts were severely handicapped by inconvenient and insensitive assays for the hormone, and the attempts failed to produce unequivocal proof of the existence of TPO. With the availability of in vitro megakaryocyte differentiation assays in the 1980s, additional purifications were attempted; however, while some claims were made of its biological activities, attempts to produce a cDNA for TPO, the sine qua non of the existence of a protein, also failed.Occasionally in science, a finding from one field, although by itself important, can have a catalytic effect on a seemingly unrelated area of research. The discovery and characterization of the murine myeloproliferative leukaemia virus (MPLV) had such an influence on the search for TPO. The virus causes an acute myeloproliferative syndrome in infected mice (Wendling et al, 1986). In 1990, the responsible oncogene (v-mpl, now termed Mpl) was cloned, and the protooncogene (c-mpl, also now termed Mpl) obtained 2 years later (Souyri et al, 1990;Vigon et al, 19...

Revealing eltrombopags promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation

“…6,7 It is well known that thrombopoietin, through binding to its receptor (c-Mpl), which is expressed by HSCs and megakaryocytes, is a critical regulator of both HSC homeostasis and megakaryopoiesis. 8 The opportunity to synthesize in vitro molecules able to mimic the physiologic effect of thrombopoietin E ltrombopag is a small, non-peptide thrombopoietin mimetic that has been approved for increasing platelet count not only in immune thrombocytopenia and Hepatitis C virus-related thrombocytopenia, but also in aplastic anemia. Moreover, this drug is under investigation for increasing platelet counts in myelodysplastic syndromes.…”

Insuficiencia hepática crónica y hemostasia

“…La unión de la TPO con su receptor c-Mpl promueve las cascadas de activación de la quinasa de Janus 2 ( JAK2) y la tirosina quinasa 2 (TYK2), además de hacer sinergia con otros estimulantes como la IL-3, IL-11 y el factor de célula progenitora (stem-cell factor), resultando en la proliferación y maduración de los megacariocitos (24,25). Panasiuk y colaboradores demostraron que en pacientes con cirrosis hepática existía una disminución de la producción de TPO y, en consecuencia, una disminución de plaquetas, así como una asociación directa entre la cuenta plaquetaria y el factor de crecimiento derivado de los hepatocitos (p <0,01) (26).…”

The thrombopoietin receptor P106L mutation functionally separates receptor signaling activity from thrombopoietin homeostasis

“…2,35 Several THPO agonists and minibodies that enhance dimerization of the receptor molecules, even before they reach the cell surface, have been recently developed. 34,45,46 Distinguishing substances that target the THPO-binding site and exert their effect by facilitating the ligand-induced conformational change from substances that enhance receptor dimerization may be helpful in predicting therapeutic success for different loss-of-function mutations.…”

“…1 In addition, disruption of the signaling pathway by inactivating THPO or c-Mpl mutations can cause serious thrombocytopenia. [2][3][4] By contrast, activating THPO or c-Mpl mutations can cause hereditary thrombocythemia (HT). [5][6][7][8][9][10][11][12] Interestingly, decreased expression of c-Mpl can also result in HT by high THPO levels, although the mechanism for this observation remains unknown.…”

“…Such a pathway of receptor maturation would also explain the rescue of the Golgi expression of the nonfunctional R102P mutant into the Golgi apparatus by coexpression of the WT receptor. 2,34,[42][43][44] With such a mechanism, the P106L-mutated receptor could form a functionally active homodimer, whose activity would not depend on cell surface expression or on rescue by coexpression of the WT receptor. Indeed, such an intracellular dimeric receptor may be active and particularly sensitive to the low level THPO that may enter the cell through trace levels of the receptor on the cell surface, as discussed above, or through unknown alternative routes (Figure 7).…”