title: Revealing eltrombopag's promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation.
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.
authors: Department of Molecular Medicine, University of Pavia, Italy.|Biotechnology Research Laboratories, IRCCS San Matteo Foundation, Pavia, Italy.
authors: Christian A
authors: CA
authors: Di Buduo
authors: Department of Molecular Medicine, University of Pavia, Italy.|Biotechnology Research Laboratories, IRCCS San Matteo Foundation, Pavia, Italy.
authors: Manuela
authors: M
authors: Currao
authors: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Italy.
authors: Alessandro
authors: A
authors: Pecci
authors: Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
authors: David L
authors: DL
authors: Kaplan
authors: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Italy.
authors: Carlo L
authors: CL
authors: Balduini
authors: Department of Molecular Medicine, University of Pavia, Italy alessandra.balduini@unipv.it.|Biotechnology Research Laboratories, IRCCS San Matteo Foundation, Pavia, Italy.|Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
authors: Alessandra
authors: A
authors: Balduini
mesh_terms: D001565:Benzoates / Q000494:pharmacology*; D015415:Biomarkers; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D053628:Receptors, Thrombopoietin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D034061:Thrombopoiesis / Q000187:drug effects*
chemical_list: D001565:Benzoates; D015415:Biomarkers; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C520809:eltrombopag