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

Abstract

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 (MPL, JAK2, CALR) and loss-of-function (LOF) activity of negative regulators (CBL, LNK) or the extrinsic MPL signaling by THPO GOF mutations leading to increased TPO synthesis. Alternatively, thrombocytosis may paradoxically result from mutations of MPL leading to an abnormal MPL trafficking, inducing increased TPO levels by alteration of its clearance. In contrast, thrombocytopenia can also result from LOF THPO or MPL 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.

Keywords: JAK2; MPL; MPLR102P; thrombocytopenia; thrombocytosis; thrombopoietin.

Figure 1

Main MPL mutations resulting in thrombocytosis or thrombocytopenia. MPL is composed of three main domains including extracellular (25–491), transmembrane, (492–513) and intracytoplasmic (514–635) domains. The extracellular domain is composed of two cytokine receptor domains (CRM) that correspond to an immunoglobulin fold of fibronectin type III. The first part of the CRM has four characteristically spaced cysteine residues, and the second part displays a WSXWS motif at the C-terminal. The intracellular domain contains box1 and box2 (in pink) and several conserved tyrosine (Y) residues. Main MPL mutations in thrombocytosis and thrombocytopenia are indicated by arrows.

Figure 2

THPO mutations found in hereditary thrombocytosis, thrombocytopenia, and bone marrow aplasia. (A) Schemes of THPO gene and thrombopoietin (TPO) protein. Mutations in THPO gene affecting either 5′UTR or splice sites (defective alternative splicing) lead to increased THPO mRNA translation and increased TPO synthesis in hereditary thrombocytosis. Mutations in coding regions of THPO affect the RBD (receptor-binding domain) and are found in hereditary thrombocytopenia or bone marrow aplasia. (B) Illustration of a pedigree with THPO mutation from a family harboring a mild thrombocytosis. (C) In silico analysis of the THPO c.13+5G>C based on five predictive algorithms of pathogenicity for splice site defects. Analysis was run using the Alamut Visual version 2.9 software (Interactive Biosoftware, Rouen, France).