Revealing eltrombopag’s promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation

Christian A. Di Buduo, Manuela Currao, Alessandro Pecci, David L. Kaplan, Carlo L. Balduini, Alessandra Balduini

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Eltrombopag 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. Despite current clinical practice, the mechanisms governing eltrombopag’s impact on human hematopoiesis are largely unknown, in part due to the impossibility of using traditional in vivo models. To investigate eltrombopag’s impact on megakaryocyte functions, we employed our established in vitro model for studying hematopoietic stem cell differentiation combined with our latest 3-dimensional silk-based bone marrow tissue model. Results demonstrated that eltrombopag favors human megakaryocyte differentiation and platelet production in a dose-dependent manner. These effects are accompanied by increased phosphorylation of AKT and ERK1/2 signaling molecules, which have been proven to be crucial in regulating physiologic thrombopoiesis. These data further clarify the different mechanisms of action of eltrombopag when compared to romiplostim, which, as we have shown, induces the proliferation of immature megakaryocytes rather than platelet production, due to the unbalanced activation of AKT and ERK1/2 signaling molecules. In conclusion, our research clarifies the underlying mechanisms that govern the action of eltrombopag on megakaryocyte functions and its relevance in clinical practice.

Original languageEnglish
Pages (from-to)1479-1488
Number of pages10
JournalHaematologica
Volume101
Issue number12
DOIs
Publication statusPublished - 2016

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Megakaryocytes
MAP Kinase Signaling System
Platelet Count
Blood Platelets
Thrombopoiesis
Thrombopoietin
Idiopathic Thrombocytopenic Purpura
Silk
Aplastic Anemia
Myelodysplastic Syndromes
Hematopoiesis
Hematopoietic Stem Cells
Hepacivirus
Thrombocytopenia
Cell Differentiation
Bone Marrow
Phosphorylation
Bone and Bones
eltrombopag
Research

ASJC Scopus subject areas

  • Hematology

Cite this

Revealing eltrombopag’s promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation. / Di Buduo, Christian A.; Currao, Manuela; Pecci, Alessandro; Kaplan, David L.; Balduini, Carlo L.; Balduini, Alessandra.

In: Haematologica, Vol. 101, No. 12, 2016, p. 1479-1488.

Research output: Contribution to journalArticle

Di Buduo, Christian A. ; Currao, Manuela ; Pecci, Alessandro ; Kaplan, David L. ; Balduini, Carlo L. ; Balduini, Alessandra. / Revealing eltrombopag’s promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation. In: Haematologica. 2016 ; Vol. 101, No. 12. pp. 1479-1488.
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