9014-42-0 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).
Check Digit Verification of cas no
The CAS Registry Mumber 9014-42-0 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 9,0,1 and 4 respectively; the second part has 2 digits, 4 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 9014-42:
(6*9)+(5*0)+(4*1)+(3*4)+(2*4)+(1*2)=80
80 % 10 = 0
So 9014-42-0 is a valid CAS Registry Number.