9014-42-0

Basic information

• Product Name: c-Mpl ligand
• Synonyms: c-Mpl ligand;Thrombopoietin
• CAS NO: 9014-42-0
• Molecular Formula: C9H19NO5
• Molecular Weight: 0
• Mol File: 9014-42-0.mol
• Article Data: 0

Chemical Properties

• Appearance: /
• CAS DataBase Reference: c-Mpl ligand(CAS DataBase Reference)
• NIST Chemistry Reference: c-Mpl ligand(9014-42-0)
• EPA Substance Registry System: c-Mpl ligand(9014-42-0)

Safety Data

• Hazardous Substances Data: 9014-42-0(Hazardous Substances Data)

Usage

Description

c-Mpl ligand, also known as Thrombopoietin (TPO), is a glycoprotein that primarily regulates thrombopoiesis, which is the production of platelets. It is produced constitutively in the liver and inductively in the bone marrow to promote the proliferation and differentiation of megakaryocytes and their progenitors, as well as maintain hematopoietic stem cells. The c-Mpl ligand signals through the c-mpl receptor and acts as an important regulator of circulating platelets.

Uses

Used in Pharmaceutical Industry:
c-Mpl ligand is used as a therapeutic agent for the treatment of immune thrombocytopenia (ITP) and other potential indications. The second generation of synthetic TPO-Mpl agonists, such as romiplostim and eltrombopag, have been approved worldwide for the treatment of ITP. These agonists stimulate the proliferation and maturation of megakaryocytes, promoting increased circulating levels of platelets in vivo.
Used in Clinical Research:
c-Mpl ligand is used as a research tool to study the mechanisms of platelet production and the role of TPO in regulating thrombopoiesis. The first generation of recombinant TPO molecules, such as PEG-rhMGDF and rhTPO, were used in clinical trials in 1995 to demonstrate the increase of platelet counts in humans for the first time. However, the trials were discontinued due to the development of a neutralizing antibody to endogenous TPO in some subjects. This research has contributed to the development of newer and safer TPO-Mpl agonists for clinical use.

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.

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).