Thrombopoietin from beginning to end

@article{Hitchcock2014ThrombopoietinFB,
  title={Thrombopoietin from beginning to end},
  author={Ian S. Hitchcock and Kenneth Kaushansky},
  journal={British Journal of Haematology},
  year={2014},
  volume={165}
}
In 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… 
View on Wiley
onlinelibrary.wiley.com
147 Citations
Highly Influential Citations
9
Background Citations
52
Methods Citations
2
Results Citations
1

147 Citations

The thrombopoietin receptor: revisiting the master regulator of platelet production
TLDR
Key aspects of TPO and MPL structure and function and their importance in receptor activation are discussed, how these are altered in hematological disorders are discussed and how a greater understanding could lead to the development of better-targeted and more efficacious therapies are considered.
The role of the thrombopoietin receptor MPL in myeloproliferative neoplasms: recent findings and potential therapeutic applications
TLDR
It is believed that MPL is an important, but challenging, therapeutic target in MPNs that requires novel strategies to interrupt the specific conformational changes induced by each mutation or pathologic interaction without compromising the key functions of wild type MPL.
Revealing eltrombopag’s promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation
TLDR
The in vitro model employed for studying hematopoietic stem cell differentiation combined with the latest 3-dimensional silk-based bone marrow tissue model demonstrated that eltrombopag favors human megakaryocyte differentiation and platelet production in a dose-dependent manner.
Genetic Alterations of the Thrombopoietin/MPL/JAK2 Axis Impacting Megakaryopoiesis
TLDR
Thrombocytosis can be due to genetic alterations that affect either the intrinsic MPL signaling through gain-of-function (GOF) activity (MPL, JAK2, CALR) and loss of function (LOF) activity of negative regulators (CBL, LNK) or the extrinsicMPL signaling by THPO GOF mutations leading to increased TPO synthesis.
Clinical applications of thrombopoietin silencing: A possible therapeutic role in COVID-19?
Role of thrombopoiesis in leishmaniasis.
Cytokine control of megakaryopoiesis
TLDR
Emphasis is given to thrombopoietin (Tpo), the major cytokine regulator of steady-state megakaryopoiesis, and its specific cell surface receptor, the Mpl protein, including normal and pathological roles as well as clinical application.
The thrombopoietin receptor P106L mutation functionally separates receptor signaling activity from thrombopoietin homeostasis.
TLDR
It is proposed that the P106L mutation functionally separates the activity of c-Mpl in downstream signaling from that in maintaining platelet homeostasis, and indicates that the activation of downstream signaling does not require correct processing, trafficking, and cell surface expression of c -Mpl, whereas the negative feedback loop controlling THPO serum levels requires cell surfaceexpression of the receptor.
The secret life of a megakaryocyte: emerging roles in bone marrow homeostasis control
TLDR
Evidence is provided that the interaction and the reciprocal regulation of megakaryocytes with the different cellular and extracellular components of the bone marrow environment after injury and their deregulation may lead to the development of a series of inherited or acquired pathologies.
Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFN-γ.
TLDR
It is shown that IFN-γ specifically prevents full engagement of thrombopoietin to its receptor (c-MPL) via steric occlusion of the low-affinity binding site, contributing to perturbation of TPO-induced signaling pathways and decreased survival of human HSPCs.
...
...

References

SHOWING 1-10 OF 142 REFERENCES
Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin
TLDR
It is demonstrated that TPO alone is the major physiological regulator of both proliferation and differentiation of hematopoietic progenitor cells into mature megakaryocytes but that T PO is not critical to the final step of platelet production.
Thrombopoietin and thrombopoietin mimetics in the treatment of thrombocytopenia.
  • D. Kuter
  • Medicine, Biology
    Annual review of medicine
  • 2009
TLDR
Although initially restricted to the second-line treatment of ITP, both new drugs that mimic the effect of TPO became available to treat thrombocytopenia in 2008 and are well tolerated, with mild headache being the most common complaint.
Thrombopoietin levels in patients with primary and reactive thrombocytosis
TLDR
The results indicate that TPO clearance by platelets–megakaryocytes is not fully operative or is not the only mechanism of TPO level regulation in primitive and reactive thrombocytosis.
Defective response to thrombopoietin and impaired expression of c‐mpl mRNA of bone marrow cells in congenital amegakaryocytic thrombocytopenia
TLDR
The results of this study suggest that the pathophysiology in CAMT may be a defective response to TPO in haemopoietic cells through impaired expression of c‐mpl mRNA.
Recombinant human thrombopoietin: basic biology and evaluation of clinical studies.
TLDR
Ongoing and future studies will help define the clinical role of recombinant TPO and TPO mimetics in the treatment of chemotherapy- and nonchemotherapy-induced thrombocytopenia.
Role of c-mpl in early hematopoiesis.
TLDR
A physiological role for TPO and its receptor, c-mpl, in regulating early hematopoiesis is demonstrated and the repopulation capacity of murine stem cell populations with respect to c-Mpl expression in a competitive repopulating assay is compared.
Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo
TLDR
The functional cloning of a murine complementary DNA encoding a ligand for the receptor encoded by the c-mpl proto-oncogene is reported, and results strongly suggest that theligand for c-Mpl is thrombopoietin.
Thrombopoietin, the Mp1 ligand, is essential for full megakaryocyte development.
TLDR
It is demonstrated that neutralizing the biological activity of Tpo eliminates MK formation in response to c-kit ligand, IL-6, and IL-11, alone and in combination, but that these reagents only partially reduceMK formation in the presence of combinations of cytokines including IL-3.
Dissecting the thrombopoietin receptor: functional elements of the Mpl cytoplasmic domain.
TLDR
These studies identify subdomains of Mpl necessary for activation of several critical signaling pathways and point to two potentially novel mechanisms of TPO-induced signal transduction, an indirect pathway to STAT5 activation and a differentiation domain that acts by limiting proliferation.
Murine thrombopoietin mRNA levels are modulated by platelet count.
TLDR
The hypothesis that TPO levels are regulated, at least in part, by modulating mRNA levels in response to platelet demand is supported.
...
...