High doses of romiplostim induce proliferation and reduce proplatelet formation by human megakaryocytes.
BACKGROUND
Romiplostim (AMG531) is a Thrombopoietin (TPO) receptor agonist with no homology with the endogenous TPO that has been used to treat patients affected by immune thrombocytopenia (ITP). Despite the use of TPO mimetics in the clinical practice, the mechanisms underlying their impact on megakaryocyte function is still unknown.


RESULTS
In this project we took advantage of an in vitro human model, that we have established in our laboratory for long time to study megakaryocyte development from human cord blood-derived progenitor cells, and we demonstrated that increasing doses of AMG531 (100 to 2000 ng/mL) determine a progressive increase of megakaryocyte proliferation with a parallel decrease in megakaryocyte ploidy and capacity of extending proplatelets. Most importantly, these differences in megakaryocyte function seemed to be correlated to modulation of AKT phosphorylation.


CONCLUSIONS
Overall our results shed new light on the mechanisms and on the relevance of dosage related to AMG531 impact on megakaryocyte function.
Department of Molecular Medicine, Biotechnology Laboratories, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy.
Manuela
M
Currao
Carlo L
CL
Balduini
Alessandra
A
Balduini
D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects*; D011003:Ploidies; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013926:Thrombopoietin / Q000494:pharmacology*
D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim