The Role of Neutrophilic Granulocytes in Philadelphia Chromosome Negative Myeloproliferative Neoplasms

Abstract

Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are composed of polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The clinical picture is determined by constitutional symptoms and complications, including arterial and venous thromboembolic or hemorrhagic events. MPNs are characterized by mutations in JAK2, MPL, or CALR, with additional mutations leading to an expansion of myeloid cell lineages and, in PMF, to marrow fibrosis and cytopenias. Chronic inflammation impacting the initiation and expansion of disease in a major way has been described. Neutrophilic granulocytes play a major role in the pathogenesis of thromboembolic events via the secretion of inflammatory markers, as well as via interaction with thrombocytes and the endothelium. In this review, we discuss the molecular biology underlying myeloproliferative neoplasms and point out the central role of leukocytosis and, specifically, neutrophilic granulocytes in this group of disorders.

Keywords: chronic inflammation; myeloproliferative neoplasms; neutrophilic granulocytes.

Figure 1

Schematic overview of hallmark mutations in MPN. JAK2 lies downstream of the EPO receptor, the thrombopoietin receptor (MPL), and the G-CSF receptor. The activation of JAK2 by a JAK2V617F or a JAK2 exon 12 mutations, therefore, enhances signaling downstream of pathways that would normally be activated by the growth factors for erythropoiesis, thrombopoiesis, or granulopoiesis. An activating mutation in MPL leads to increased signaling through the thrombopoietin (TPO)-thrombopoietin receptor-(MPL)-axis. Similarly, a mutation in the chaperone protein CALR leads to a constitutive activation of MPL upon binding of CALR to MPL in the endoplasmic reticulum (ER).