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Description
Thrombopoietin is a glycoprotein that primarily regulates thrombopoiesis, that is, platelet production. Produced constitutively in
the liver and inductively in the bone marrow to promote
the proliferation and differentiation of megakaryocytes and
their progenitors, and maintain hematopoietic stem cells. After the nature of platelets was described by Donne,
Addison, Osler, and Bizzozero in the 1800s, Wright reported that the origin of human platelets (thrombocytes) was the bone marrow. The tentative name thrombopoietin (TPO) was proposed for a humoral factor of
platelet production, independently by Komiya and by
Kelemen. It was not apparent whether TPO activity
was identical to in vitro activity defined as a megakaryocyte colony stimulating factor. TPO molecules were
finally identified simultaneously by independent
research groups. Concurrently,
c-Mpl (Mpl) expressing megakaryocytes was confirmed as the TPO receptor.
Uses
The clinical trials of a first generation of recombinant
TPO molecules (i.e., PEG-rhMGDF and rhTPO) started in
1995, and proved the increase of platelet counts in
humans for the first time, but were discontinued due to
the development of a neutralizing antibody to endogenous TPO in 13 human subjects in the PEG-MGDF study.
The second generation of synthetic TPO-Mpl agonists
(romiplostim and eltrombopag) followed, and was
approved throughout the world for the treatment of
immune thrombocytopenia (ITP). Other indications are
further considered.
Uses
TPO stimulates the proliferation and maturation of megakaryocytes and promotes increased circulating levels of platelets in vivo. TPO signals through the c-mpl receptor and acts as an important regulator of circulating platelets
Biochem/physiol Actions
Thrombopoeitin is a primary regulatory factor for megakaryocytopoiesis and thrombopoiesis. The mature form of TPO is a highly conserved glycoprotein, showing homology among various mammals. It is produced by liver and kidney cells. TPO stimulates growth and maturation of megakaryocytes and megakaryocytic colonies from bone marrow cultures. TPO binds and activates an 68-78 kDa glycoprotein receptor belonging to the GH family of cytokine receptors, a family that includes receptors to growth hormone (GH), erythropoietin (EPO), and prolactin (PRL). Like GH and EPO, TPO may bind to its receptor at two distinct sites, initiating receptor dimerization and activation. Analysis of mRNA indicates also the existence of a novel truncated and potentially soluble form of TPO receptor. The viral oncogene v-mlp of the myeloproliferative leukemia virus (MPLV) contains the gene sequence for the entire cytoplasmic and transmembrane domains and a portion of the extracellular domain of c-mlp (TPO receptor).
Questions And Answer
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Properties
Native TPOs originally isolated were truncated N-terminal domains (17–36 kDa). The size distribution of circulating human TPO in patients with various hematologic disorders does not differ markedly, indicating that the truncation of TPO is not related to disease pathophysiology.; -
Receptors
Mpl is a glycoprotein (~80 kDa) that belongs to a member of the cytokine receptor superfamily. The sequence contains a retroviral oncogene (v-mpl) that induces multilineage myeloproliferative leukemia in mice. A human Mpl gene is located in the chromosome 1p34.2. Splicing variants of soluble (S-form) and truncated (K-form) types are identified. Positions of cysteine are mostly conserved, but the disulfide bonds are not fully confirmed. The motifs of WSXWS, and box 1 and box 2 are conserved among species. The dimeric Mpl binding to TPO activates a number of secondary messengers that promote cell proliferation, differentiation, and survival in megakaryocytes/platelets and leukemic cell lines through the JAK2-STAT3/5 signaling cascade activating PI3K and/or RAS/MAPK.; -
Agonists
Various agonists have been developed. After the development of pegylated recombinant human megakaryocyte growth and development factor (PEGrhMGDF) produced by E. coli and recombinant human TPO (rhTPO) produced by CHO cells, an artificial mimetic peptide of romiplostim (AMG-531) and an orally available small molecule of eltrombopag (SB-497115) were approved as therapeutic agents. Other nonpeptide agonists (AKR-501 (E5501), LGA-4665, NIP-004, NIP022, butyzamide, ALXN4100TPO) and several agonist antibodies or related derivatives such as MA01G4344U and VB22B were also reported.; -
Biological functions
TPO binds to Mpl on the surface of megakaryocyte/ platelet progenitors to stimulate their proliferation and differentiation. One mature megakaryocyte with a higher ploidy class is capable of releasing thousands of platelets. TPO is also produced by osteoblastic/stromal cells in the bone marrow microenvironment, and maintains hematopoietic stem cells that express Mpl. Cultured megakaryocytes derived from either peripheral or cord blood express a single class of high-affinity Mpl (2000 sites with Kd=90 pM and 180 sites per cell with Kd=125 pM), respectively, whereas single peripheral platelets display 20–30 sites (Kd=20–60 pM).; -
Clinical implications
TPO acts primarily on megakaryocytes as a late-acting differentiation factor to platelet production as well as the maintenance of hematopoietic stem cells. Stimulating TPO-Mpl cellular signaling is effective for the treatment of thrombocytopenia caused by various diseases and therapies, including chemotherapy and irradiation. Likewise, TPO is expected to be applicable to hematopoietic stem cell expansion.Based on the physiology of the TPO-Mpl system, however, TPO does not induce the immediate release of platelets from megakaryocytes.;
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