AUTHOR=Plo Isabelle , Bellanné-Chantelot Christine , Mosca Matthieu , Mazzi Stefania , Marty Caroline , Vainchenker William 

TITLE=Genetic Alterations of the Thrombopoietin/MPL/JAK2 Axis Impacting Megakaryopoiesis

JOURNAL=Frontiers in Endocrinology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2017.00234

DOI=10.3389/fendo.2017.00234

ISSN=1664-2392

ABSTRACT=<p>Megakaryopoiesis is an original and complex cell process which leads to the formation of platelets. The homeostatic production of platelets is mainly regulated and controlled by thrombopoietin (TPO) and the TPO receptor (MPL)/JAK2 axis. Therefore, any hereditary or acquired abnormality affecting this signaling axis can result in thrombocytosis or thrombocytopenia. Thrombocytosis can be due to genetic alterations that affect either the intrinsic MPL signaling through gain-of-function (GOF) activity (<italic>MPL, JAK2, CALR</italic>) and loss-of-function (LOF) activity of negative regulators (<italic>CBL, LNK</italic>) or the extrinsic MPL signaling by <italic>THPO</italic> GOF mutations leading to increased TPO synthesis. Alternatively, thrombocytosis may paradoxically result from mutations of <italic>MPL</italic> leading to an abnormal MPL trafficking, inducing increased TPO levels by alteration of its clearance. In contrast, thrombocytopenia can also result from LOF <italic>THPO</italic> or <italic>MPL</italic> mutations, which cause a complete defect in MPL trafficking to the cell membrane, impaired MPL signaling or stability, defects in the TPO/MPL interaction, or an absence of TPO production.</p>