The Role of Neutrophilic Granulocytes in Philadelphia Chromosome Negative Myeloproliferative Neoplasms.

Dominik Kiem,Teresa Magnes,Thomas Melchardt,Alexander Egle,Richard Greil,Sandro Wagner

doi:10.3390/ijms22179555

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.

Highlights

We will focus strictly on the three most frequent Philadelphia chromosome (Ph) negative disease entities: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), which are mostly associated with mutations in either the Janus kinase 2 (JAK2) gene, the myelproliferative leukemia virus oncogene (MPL), or the calreticulin (CALR) gene [2,3]
Since chronic myeloid leukemia (CML) arises from a chromosome 9:22 translocation, commonly referred to as the Philadelphia chromosome, which displays a significantly different biology compared to PV, ET, and PMF, we omitted the further discussion of that entity in our review [4]
It is important to note that JAK2V617F mutations with a low allelic fraction can be found in a significant number of healthy subjects, are a common cause for clonal hematopoiesis of indeterminate potential (CHIP) [29] that may precede clinical disease onset by many years [30]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. We will focus strictly on the three most frequent Philadelphia chromosome (Ph) negative disease entities: PV, ET, and PMF, which are mostly associated with mutations in either the Janus kinase 2 (JAK2) gene, the myelproliferative leukemia virus oncogene (MPL), or the calreticulin (CALR) gene [2,3]. These three entities share common features in their biology and pathophysiology and lead to partially overlapping clinical presentations. Since CML arises from a chromosome 9:22 translocation, commonly referred to as the Philadelphia chromosome, which displays a significantly different biology compared to PV, ET, and PMF, we omitted the further discussion of that entity in our review [4]

Clinical Picture and Course of Disease

Schematic

Inflammation

Phlebotomy and Cytoreductive Therapy

Interferon

Findings

JAK Inhibitors